AU732995B2 - Carbapenem antibacterial compounds, compositions and methods of treatment - Google Patents

Description

WO 99/20270 PCT/US98/22111 -1 TITLE OF THE INVENTION CARBAPENEM ANTIBACTERIAL COMPOUNDS, COMPOSITIONS AND METHODS OF TREATMENT BACKGROUND OF THE INVENTION Infections caused by methicillin resistant Staphylococcus aureus (MRSA) and related gram positive pathogens are a growing medical concern. Vancomycin, a glycopeptide antibiotic, is currently the agent of choice for combating these infections which are predominantly encountered in hospital settings. With the increased usage of Vancomycin, the emergence of resistant stains of staphylococci is inevitable, and the first confirmed report of vancomycin resistance in Staphylococcus epidermidis was disclosed at the 36th Interscience Conference on Antimicrobial Agents and Chemotherapy, New Orleans, Louisiana, 1996. Consequently, there is a dire need to develop new agents with an alternative mode of action.

The present invention relates to novel tricyclic carbapenem compounds (trinems) in which the lipophilic side-chain necessary for anti-MRSA activity replaces the common simple ether based substitutents found in EPO 416,953, substituted carbon atoms found in EPO 507,313, and substituted amines found in WO9523149. The antibacterial compounds of the present invention thus comprise an important contribution to therapy for treating infections caused by these difficult to control pathogens. There is an increasing need for agents effective against such pathogens (MRSA/MRCNS) which are at the same time relatively free from undesirable side effects.

WO 99/20270 PCT/US98/2211 -2 SUMMARY OF THE INVENTION The present invention relates to anti-MRSA tricyclic carbapenem antibiotics containing aromatic based side-chains. The sidechain imparts MRS activity previously unassociated with the trinem skeleton.

The compounds of the invention are represented by formula I: Rrr H H

H

3

C

O N z S CO 2

M

or a pharmaceutically acceptable salt thereof, wherein: Z represents

R

3

(R)

3

(R)

3 or -s (R) 3 X (R) 3 N-S d* b* O O a*/ c* X represents CH 2 CHR, C=CHR, O, S, SO, SO 2 CO, CO 2 OCO, or NR;

CO

2 M represents a carboxylic acid, a carboxylate anion counter balanced by a counterion, a pharmaceutically acceptable ester group or a carboxylic acid protected by a protecting group; WO 99/20270 PCT/US98/22111 -3 Rrr represents hydrogen, -C1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R i groups; P represents hydrogen, hydroxyl, F or hydroxyl protected by a hydroxyl-protecting group; each R is independently selected from: -Q; hydrogen; halo; -CN; -NO 2 -NRaRb; -ORc; -SRc; -C(O)NRaRb; C(O)ORh; -S(O)Rc; -SO 2 Rc; -SO 2 NRaRb; -NRaSO 2 Rb; -C(O)Ra; OC(O)Ra; -OC(O)NRaRb; -NRaC(O)NRbRc; -NRaCO 2 Rh; -OCO 2 Rh; NRaC(O)Rb; -C1- 6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four Rd groups; and -C3- 7 cycloalkyl, unsubstituted or substituted with one to four Rd groups; with the proviso that at least one R is present which contains at least one positive charge; each Ra, Rb and Rc independently represents hydrogen, -C1- 6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four Rd groups, or -C3- 7 cycloalkyl, unsubstituted or substituted with one to four Rd groups; or Ra and Rb taken together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one or more of O, S, NRc, with Rc as defined above, or said ring being unsubstituted or substituted with one to four R i groups; or Rb and Rc taken together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one to three of O, S, NRa, with Ra as defined above, or said ring being unsubstituted or substituted with one to four R i groups; each Rd independently represents halo; -CN; -NO 2 -NReRf; -ORg; -SRg; -CONReRf; -COORg; -SORg; -SO 2 Rg; -SO 2 NReRf; NReSO 2 Rf; -CORe; -NRe CORf; -OCORe; -OCONReRf; -NReCONRfRg; NReCO 2 Rh; -OC0 2 Rh; -C(NRe)NRfRg; -NReC(NH)NRfRg; -NReC(NRf)Rg; or -Q; WO 99/20270 PCT/US98/22111 -4- Re, Rf and Rg represent hydrogen; -C1-6 straight- or branched-chain alkyl unsubstituted or substituted with one to four R i groups; or Re and R f taken together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one to three of O, S, or NRg with Rg as defined above, said ring being unsubstituted or substituted with one to four R i groups; each Ri independently represents halo; -CN; -N02; phenyl; -NHS0 2 Rh; -ORh, -SRh; -N(Rh) 2 -N+(Rh) 3 -C(0)N(Rh) 2

SO

2 N(Rh) 2 heteroaryl; heteroarylium; -C0 2 Rh; -C(0)Rh; -OCORh; NHCORh; guanidinyl; carbamimidoyl or ureido; each Rh independently represents hydrogen, a -Ci-6 straight or branched-chain alkyl group, a -C 3

-C

6 cycloalkyl group or phenyl, or when two Rh groups are present, said Rh groups may be taken in combination and represent a 4-6 membered saturated ring, optionally interrupted by one or two of O, S, S02, NH and NCH3; Q is selected from the group consisting of: (CH2)b N N Ne N-R x and N L (CH 2 )a wherein: a and b are 1, 2 or 3; L- is a pharmaceutically acceptable counterion; a represents O, S or NRs; P, 8, X, and o represent CRt, N or N+Rs, provided that no more than one of 3, 8, X, p. and o is N+RS; WO 99/20270 PCT/US98/22111 R* is selected from the group consisting of: I I and z d'y eg e- g wherein: d represents O, S or NRk; e, g, x, y and z represent CRm, N or N+Rk, provided that no more than one of e, g, x, y and z in any given structure represents N+Rk; Rk represents hydrogen; -C 1 -6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R i groups; or

(CH

2 )nQ where n 1, 2 or 3 and Q is as previously defined; each Rm independently represents a member selected from the group consisting of: hydrogen; halo; -CN; -NO 2 -NRnRo; -ORn;

SR

n -CONRnRo; -COORh; -SOR n

-SO

2

R

n

-SO

2 NRnRo; -NRnSO 2 Ro; CORn; -NRnCORo; -OCORn; -OCONRnRo; -NRnCO 2 Rh; -NRnCONRoRh;

-OCO

2 Rh; -CNRnNRoRh; -NRnCNHNRoRh; -NRnC(NRo)Rh; -C1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R i groups; -C3- 7 cycloalkyl, unsubstituted or substituted with one to four R i groups; and -(CH 2 )nQ where n and Q are as defined above;

R

n and Ro represent hydrogen, phenyl; -C1-6 straight- or branched-chain alkyl unsubstituted or substituted with one to four R i groups; each Rs independently represents hydrogen; phenyl or -C1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R i groups; each Rt independently represents hydrogen; halo; phenyl; -CN; -NO 2 -NRuRv; -ORu; -SRu; -CONRuRv; -COORh; -SORu; -SO 2 Ru;

-SO

2 NRuRv; -NRuSO 2 RV; -CORu; -NRuCORv; -OCORu; -OCONRuRV; WO 99/20270 PCT/US98/22111 c' -6 -NRuCO 2 Rv; -NRuCONRvRw; -OCO 2 RV; -C1-6 straight- or branchedchain alkyl, unsubstituted or substituted with one to four R i groups; Ru and R v represent hydrogen or -Ci-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R i groups; or Ru and Rv together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one or more of O, S, NRw or said ring being unsubstituted or substituted with one to four R i groups; each R w independently represents hydrogen; -C1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R i groups; C3-6 cycloalkyl optionally substituted with one to four R i groups; phenyl optionally substituted with one to four Ri groups, or heteroaryl optionally substituted with 1-4 R i groups; or Rh and R w taken together with any intervening atoms represent a 5-6 membered saturated ring, optionally interrupted by one or two of O, S, S02, NH or NCH3; Rx represents hydrogen or a C1-8 straight- or branchedchain alkyl, optionally interrupted or terminated by one or two of O, S, SO, SO2, NRw, N+RhRw, or said chain being unsubstituted or substituted with one to four of halo, CN, N02, ORw, SRw, SORw, SO2Rw, NRhRw, N+(Rh) 2 RW, C(0)NRhRw, SO 2 NRhRw, CO2Rw, OC(O)RW, OC(0)NRhRw, NRhC(O)Rw, NRhC(0)NRhRW, phenyl or heteraryl, said phenyl and heteroaryl being optionally substituted with from one to four Ri groups or with one to two C1-3 straight- or branched- chain alkyl groups, said alkyl groups being unsubstituted or substituted with one to four R i groups; RY and Rz represent hydrogen; phenyl; -C1-6 straight or branched chain alkyl, unsubstituted or substituted with one to four R i groups, and optionally interrupted by O, S, NRW, N+RhRw or or Rx and RY together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by O, S, S02, NRw N+RhR or unsubstituted or substituted with 1 4 Ri groups, and when Rx and RY together represent a 4-6 membered ring as defined above, Rz is as defined above or Rz represents an additional saturated 4-6 membered ring fused to the ring represented by

R

x nd RY taken together, optionally interrupted by O, S, NRW or said rings being unsubstituted or substituted with one to four R' groups.

Pharmaceutical compositions and methods of treatment are also included herein.

c Also included are: compounds represented by formula I as described above or i pharmaceutical compositions thereof when used for treating or preventing a bacterial 15 infection in a mammalian patient and use of compounds represented by formula I as described above in the manufacture of a medicament for treating or preventing a bacterial infection in a mammalian patient.

*2

*S.

[RALIBAA]08619.doc:ACR WO 99/20270 PCT/US98/22111 -8 DETAILED DESCRIPTION OF THE INVENTION The invention is described herein in detail using the terms defined below unless otherwise specified.

Carboxylate anion refers to a negatively charged group

COO-.

The term "alkyl" refers to a monovalent alkane (hydrocarbon) derived radical containing from 1 to 10 carbon atoms unless otherwise defined. It may be straight, branched or cyclic. Preferred alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, cyclopentyl and cyclohexyl. When substituted, alkyl groups may be substituted with up to four substituent groups, selected from Rd and Ri, as defined, at any available point of attachment. When the alkyl group is said to be substituted with an alkyl group, this is used interchangeably with "branched alkyl group".

Cycloalkyl is a specie of alkyl containing from 3 to carbon atoms, without alternating or resonating double bonds between carbon atoms. It may contain from 1 to 4 rings which are fused.

The term "alkenyl" refers to a hydrocarbon radical straight, branched or cyclic containing from 2 to 10 carbon atoms and at least one carbon to carbon double bond. Preferred alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl.

The term "alkynyl" refers to a hydrocarbon radical straight or branched, containing from 2 to 10. carbon atoms and at least one carbon to carbon triple bond. Preferred alkynyl groups include ethynyl, propynyl and butynyl.

Aryl refers to aromatic rings phenyl, substituted phenyl and the like, as well as rings which are fused, naphthyl, phenanthrenyl and the like. An aryl group thus contains at least one ring having at least 6 atoms, with up to five such rings being present, containing up to 22 atoms therein, with alternating (resonating) double bonds between adjacent carbon atoms or suitable heteroatoms.

The preferred aryl groups are phenyl, naphthyl and phenanthrenyl.

WO 99/20270 PCT/US98/22111 -9 Aryl groups may likewise be substituted as defined. Preferred substituted aryls include phenyl and naphthyl.

The term "heteroaryl" refers to a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10 atoms, containing at least one heteroatom, 0, S or N, in which a carbon or nitrogen atom is the point of attachment, and in which one or two additional carbon atoms is optionally replaced by a heteroatom selected from O or S, and in which from 1 to 3 additional carbon atoms are optionally replaced by nitrogen heteroatoms, said heteroaryl group being optionally substituted as described herein. Examples of this type are pyrrole, pyridine, oxazole, thiazole and oxazine. Additional nitrogen atoms may be present together with the first nitrogen and oxygen or sulfur, giving, thiadiazole. Examples include the following: WO 99/20270 WO 9920270PCTIUS98/22111I 10

CONH

pyrrole (pyrrolyl) r- NH imidazole (imidazolyl) N thiazole (thiazolyl) r\0 oxazole (oxazolyl) furan (furyl) thiophene (thienyl)

N-W

NzzNH

NH

triazole (triazolyi) pyrazole (pyrazolyl) isoxazole (isoxazolyl) N Nisothiazole (isothiazolyl) pyridine (pyridinyl)

(N

pyrazine (pyrazinyl)

N

pyrimidine (pyrimidinyl) pyridazine (pyridazinyl) N 1 triazine (triazinyl) Heteroarylium. refers to heteroaryl groups bearing a quaternary nitrogen atom and thus a positive charge. Examples include the following: WO 99/20270 PCT/US98/22111 -11

-N

N

N/N--CH3

'N;,NCH

3 N- CH3

H

3

K-

OH

N+

CH

6H 3

N/

N

N-N

N

-7N

I

CH3 N-N

CH

3 A

N"-

When a charge is shown on a particular nitrogen atom in a ring which contains one or more additional nitrogen atoms, it is understood that the charge may reside on a different nitrogen atom in the ring by virtue of charge resonance that occurs.

IN-CyCH 3

N:N-CH,

3 and S/N-CH3

,NN-CH

3 N- N OH WO 99/20270 PCT/US98/22111 12 The term "heterocycloalkyl" refers to a cycloalkyl group (nonaromatic) in which one of the carbon atoms in the ring is replaced by a heteroatom selected from O, S or N, and in which up to three additional carbon atoms may be replaced by hetero atoms.

The terms "quaternary nitrogen" and "positive charge" refer to tetravalent, positively charged nitrogen atoms including, the positively charged nitrogen in a tetraalkylammonium group g. tetramethylammonium), heteroarylium, N-methylpyridinium), basic nitrogens which are protonated at physiological pH, and the like. Cationic groups thus encompass positively charged nitrogen-containing groups, as well as basic nitrogens which are protonated at physiologic pH.

The term "heteroatom" means O, S or N, selected on an independent basis.

Halogen and "halo" refer to bromine, chlorine, fluorine and iodine.

Alkoxy refers to C 1

-C

4 alkyl-O-, with the alkyl group optionally substituted as described herein.

When a group is termed "substituted", unless otherwise indicated, this means that the group contains from 1 to 4 substituents thereon. With respect to R, Ra, Rb and R c the substituents available on alkyl groups are selected from the values of Rd. Many of the variable groups are optionally substituted with up to four Ri groups.

With respect to Re, R f and Rg, when these variables represent substituted alkyl, the substituents available thereon are selected from the values of R i When a functional group is termed "protected", this means that the group is in modified form to preclude undesired side reactions at the protected site. Suitable protecting groups for the compounds of the present invention will be recognized from the present application taking into account the level of skill in the art, and with reference to standard textbooks, such as Greene, T. W. et al. Protective Groups in Organic Synthesis Wiley, New York (1991).

WO 99/20270 PCT/US98/22111 13 Examples of suitable protecting groups are contained throughout the specification.

In some of the carbapenem compounds of the present invention, M is a readily removable carboxyl protecting group, and/or P represents a hydroxyl which is protected by a hydroxylprotecting group. Such conventional protecting groups consist of known groups which are used to protectively block the hydroxyl or carboxyl group during the synthesis procedures described herein.

These conventional blocking groups are readily removable, i.e., they can be removed, if desired, by procedures which will not cause cleavage or other disruption of the remaining portions of the molecule. Such procedures include chemical and enzymatic hydrolysis, treatment with chemical reducing or oxidizing agents under mild conditions, treatment with a transition metal catalyst and a nucleophile and catalytic hydrogenation.

Examples of carboxyl protecting groups include allyl, benzhydryl, 2-naphthylmethyl, benzyl, silyl such as t-butyldimethylsilyl (TBS), phenacyl, p-methoxybenzyl, o-nitrobenzyl, p-methoxyphenyl, p-nitrobenzyl, 4-pyridylmethyl and t-butyl.

Examples of suitable hydroxyl protecting groups include triethylsilyl (TES), t-butyldimethylsilyl(TBS), t-butyldiphenylsilyl (DPTBS), o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, benzyloxycarbonyl, allyloxycarbonyl, t-butyloxycarbonyl, 2,2,2-trichloroethyloxycarbonyl and the like.

The carbapenem compounds of the present invention are useful per se and in their pharmaceutically acceptable salt and ester forms for the treatment of bacterial infections in animal and human subjects. The term "pharmaceutically acceptable ester, salt or hydrate," refers to those salts, esters and hydrated forms of the compounds of the present invention which would be apparent to the pharmaceutical chemist. those which are substantially non-toxic and which may favorably affect the pharmacokinetic properties of said compounds, such as palatability, absorption, distribution, WO 99/20270 PCT/US98/22111 -14metabolism and excretion. Other factors, more practical in nature, which are also important in the selection, are cost of the raw materials, ease of crystallization, yield, stability, solubility, hygroscopicity and flowability of the resulting bulk drug.

Conveniently, pharmaceutical compositions may be prepared from the active ingredients in combination with pharmaceutically acceptable carriers. Thus, the present invention is also concerned with pharmaceutical compositions and methods of treating bacterial infections utilizing as an active ingredient the novel carbapenem compounds.

With respect to -CO2M, which is attached to the carbapenem nucleus at position 3, this represents a carboxylic acid group (M represents a carboxylate anion (M represents a negative charge), a pharmaceutically acceptable ester (M represents an ester forming group) or a carboxylic acid protected by a protecting group (M represents a carboxyl protecting group).

The pharmaceutically acceptable salts referred to above may take the form -COOM, where M is a negative charge, which is balanced by a counterion, an alkali metal cation such as sodium or potassium. Other pharmaceutically acceptable counterions may be calcium, magnesium, zinc, ammonium, or alkylammonium cations such as tetramethylammonium, tetrabutylammonium, choline, triethylhydroammonium, meglumine, triethanolhydroammonium, etc.

The pharmaceutically acceptable salts referred to above also include acid addition salts. Thus, the Formula I compounds can be used in the form of salts derived from inorganic or organic acids.

Included among such salts are the following: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, WO 99/20270 PCT/US98/22111 15 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate and undecanoate.

The pharmaceutically acceptable esters are such as would be readily apparent to a medicinal chemist, and include, for example, those described in detail in U.S. Pat. No. 4,309,438.

Included within such pharmaceutically acceptable esters are those which are hydrolyzed under physiological conditions, such as pivaloyloxymethyl, acetoxymethyl, phthalidyl, indanyl and methoxymethyl, and others described in detail in U.S. Pat. No.

4,479,947. These are also referred to as "biolabile esters".

Biolabile esters are biologically hydrolizable, and may be suitable for oral administration, due to good absorption through the stomach or intenstinal mucosa, resistance to gastric acid degradation and other factors. Examples of biolabile esters include compounds in which M represents an alkoxyalkyl, alkylcarbonyloxyalkyl, alkoxycarbonyloxyalkyl, cycloalkoxyalkyl, alkenyloxyalkyl, aryloxyalkyl, alkoxyaryl, alkylthioalkyl, cycloalkylthioalkyl, alkenylthioalkyl, arylthioalkyl or alkylthioaryl group. These groups can be substituted in the alkyl or aryl portions thereof with acyl or halo groups. The following M species are examples of biolabile ester forming moieties.: acetoxymethyl, 1-acetoxyethyl, 1-acetoxypropyl, pivaloyloxymethyl, 1-isopropyloxycarbonyloxyethyl, 1-cyclohexyloxycarbonyloxyethyl, phthalidyl and (2-oxo-5-methyl-1,3-dioxolen-4-yl)methyl.

L- can be present or absent as necessary to maintain the appropriate charge balance. When present, L- represents a pharmaceutically acceptable counterion. Most anions derived from inorganic or organic acids are suitable. Representative examples of such counterions are the following: acetate, adipate, aminosalicylate, anhydromethylenecitrate, ascorbate, aspartate, benzoate, benzenesulfonate, bromide, citrate, camphorate, camphorsulfonate, chloride, estolate, ethanesulfonate, fumarate, glucoheptanoate, gluconate, glutamate, lactobionate, malate, maleate, mandelate, WO 99/20270 PCT/US98/22111 -16 methanesulfonate, pantothenate, pectinate, phosphate/diphosphate, polygalacturonate, propionate, salicylate, stearate, succinate, sulfate, tartrate and tosylate. Other suitable anionic species will be apparent to the ordinarily skilled chemist.

Likewise, when L- represents a specie with more than one negative charge, such as malonate, tartrate or ethylenediaminetetraacetate (EDTA), an appropriate number of carbapenem molecules can be found in association therewith to maintain the overall charge balance and neutrality.

Rrr

R

H H R

H

3

C

N R O N Ia CO 2 M ^S 0 A subset of compounds of formula Ia which is of interest relates to those compounds where CO2M represents a carboxylate anion. Hence, M in this instance represents a negative charge which will be balanced by a positively charged group, such as in the positively charged R group. Likewise, if the positively charged R group contains more than one positive charge, a negatively charged counterion may be present which in combination with the carboxylate anion, provides overall charge neutrality.

Another subset of compounds of formula Ia which is of interest relates to compounds wherein one R represents a group which contains a positively charged moiety, and the remaining R groups are selected from hydrogen and C1-6 straight or branched chain alkyl, unsubstituted or substituted with one to four Rd groups.

More particularly, this subset of interest includes compounds of formula Ia wherein one R represents a group containing a positively charged moiety and the remaining R groups are hydrogen.

WO 99/20270 PCT/US98/22111 17 With respect to the positively charged moiety or moieties that are contained in one or more R groups, it is preferred that from 1-3 positive charges be present, and most preferably two positive charges be present, balanced by the carboxylate anion and a negatively charged counterion.

Another subset of compounds which is of interest is represented by formula Ia wherein one R group represents a -C1-6 straight or branched chain alkyl group, substituted with one to four Rd groups, wherein one Rd group represents or Q. Hence, a positively charged moiety or Q is attached to an alkyl group.

Another group of compounds of interest is represented by formula Ia wherein Q is selected from the group consisting of: (CH2)b N and N NR /X L (CH 2 )a More particularly, the group of compounds which is of interest is represented by formula I wherein Q represents: (CH2)b I N N-Rx L (CH 2 )a Within this subset of compounds, L- a and b are as originally defined, and Rx is as originally defined, and represents a member selected from the group consisting of: hydrogen or a C1-8 straight- or branched- chain alkyl, optionally interrupted or terminated by one or two of O, S, SO, S02, NRW, N+RhRw, or said chain being unsubstituted or substituted with one to four of halo, CN, N02, ORw, SRw, SORW, S0 2 Rw, NRhRW, N+(Rh) 2 Rw, C(O)NRhRw, SO2NRhRw, CO2Rw, OC(O)Rw, OC(O)NRhRw, NRhC(0)Rw, NRhC(O)NRhRw, or a WO 99/20270 PCT/US98/22111 -18 phenyl or heteroaryl group which is in turn optionally substituted with from one to four Ri groups or with one to two C1-3 straight- or branched- chain alkyl groups, said alkyl groups being unsubstituted or substituted with one to four R i groups.

Another group of compounds of interest is represented by formula I wherein Q represents -N+RxRYRz, wherein Rx, RY and Rz are as originally defined.

Another group of compounds of interest is represented by formula I wherein one R* group is present and is selected from: 11 and -Z 'd d'y e Within this subset, d represents NRk; Rk represents -C1-6 straight or branched chain alkyl; and e, g, x and y represent CRm or N+Rk, with Rk as defined above and Rm representing hydrogen.

A preferred subset of compounds of formula I which is of particular interest relates to compounds represented by formula I wherein: Z represents a*; CO2M represents a carboxylate anion; one R group which is attached to the naphthosultam platform contains at least one positively charged moiety, and the remaining R groups are selected from hydrogen and C1-6 straight or branched chain alkyl, unsubstituted or substituted with one to four Rd groups; Rd is as originally defined; Rh represents hydrogen or a C1-6 straight or branched chain alkyl group; WO 99/20270 PCT/US98/22111 -19 Q is selected from the group consisting of:

(CH

2 )b N -N and L (CH 2 )a wherein a and b are as originally defined, and R x represents a member selected from the group consisting of: hydrogen or a C1-8 straight- or branched- chain alkyl, optionally interrupted or terminated by one or two of O, S, SO, S02, NRw, N+RhRw, or said chain being unsubstituted or substituted with one to four of halo, CN, N02, ORw, SRW, SORw, SO 2

RW,

NRhRw, N+(Rh) 2 RW, C(0)NRhRw, SO2NRhRw, CO2R

W

OC(O)Rw, OC(O)NRhRw, NRhC(O)Rw, NRhC(O)NRhRw, phenyl or heteroaryl, said phenyl or heteroaryl group being optionally substituted with from one to four Ri groups or with one to two C1-3 straight- or branched- chain alkyl groups, said alkyl groups being unsubstituted or substituted with one to four Ri groups; R* is selected from: and d'y e-g wherein d represents NRk; Rk represents -C 1 6 straight or branched chain alkyl; and e, g, x and y represent CRm or N+Rk, with Rk as defined above and R m representing hydrogen.

Within this subset, all other variables are as originally defined with respect to formula I.

Another more preferred subset of compounds is represented by formula Ib: WO 99/20270 PCT/US98/22111 HO Rrr HH

R

H

3

C

N NR CO2M S Ib 0.

0 or a pharmaceutically acceptable salt thereof, wherein: CO2M represents a carboxylate anion; one R group is attached to the naphthosultam platform which contains a positively charged moiety, and the other R group is selected from hydrogen and C1-6 straight or branched chain alkyl, unsubstituted or substituted with one to four Rd groups; Rd is as originally defined; Q is selected from the group consisting of:

(CH

2 )b B' 1 1N'B and N /N-Rx L (CH 2 )a wherein a and b are as originally defined, and Rx represents a member selected from the group consisting of: hydrogen or a C1-8 straight- or branched- chain alkyl, optionally interrupted by one or two of O, S, SO, S02, NRw, N+RhRw, or said chain being unsubstituted or substituted with one to four of halo, CN, N02, ORW, SRW, SORW, SO2RW, NRhRw, N+(Rh) 2 Rw, C(0)NRhRw, SO2NRhRw, CO2Rw, OC(O)RW, OC(0)NRhRw, NRhC(O)Rw, NRhC(O)NRhRW, phenyl or heteroaryl, said phenyl and heteroaryl group being optionally substituted with from one to four R i groups or with one to two C1-3 straightor branched- chain alkyl groups, said alkyl groups being unsubstituted or substituted with one to four R i groups; WO 99/20270 PCT/US98/22111 -21 Rh represents hydrogen or a C1-6 straight or branched chain alkyl group;

R

w is as originally defined; R* is selected from: 11 and d d-Y e9g wherein d represents NRk; Rk represents -C1-6 straight or branched chain alkyl; and e, g, x and y represent CR m or N+Rk, with Rk as defined above and Rm representing hydrogen. Within this subset, all other variables are as originally defined with respect to formula I.

Another more preferred subset of compounds is represented by formula Ic: HO H H I R

H

3

C

0 N N

CO

2 M S Ic

R

O

or a pharmaceutically acceptable salt thereof, wherein: CO2M represents a carboxylate anion; one R group is attached to the naphthosultam platform which contains a positively charged moiety, and the other R group is selected from hydrogen, halo and C 1 -6 straight or branched chain alkyl, unsubstituted or substituted with one to four Rd groups;

R

d is as originally defined; Q is selected from the group consisting of: WO 99/20270 PCT/US98/22111 -22 (CH2)b Sand N-Rx L (CH 2 )a wherein a and b are as originally defined, and Rx represents a member selected from the group consisting of: hydrogen or a C1-8 straight- or branched- chain alkyl, optionally interrupted by one or two of O, S, SO, S02, NRw, N+RhRw, or said chain being unsubstituted or substituted with one to four of halo, CN, N02, ORw, SRw, SORW, SO2R w NRhRw, N+(Rh) 2 RW, C(O)NRhRw, SO2NRhRw, CO2R w OC(O)Rw, OC(0)NRhRw, NRhC(O)Rw, NRhC(O)NRhRw, phenyl or heteroaryl, said phenyl and heteroaryl group being optionally substituted with from one to four Ri groups or with one to two C1-3 straight or branched chain alkyl groups, said alkyl groups being unsubstituted or substituted with one to four R i groups; Rh represents hydrogen or a C1-6 straight or branched chain alkyl group;

R

w is as originally defined; R* is selected from: Sand d-y e wherein d represents NRk; Rk represents -C1-6 straight or branched chain alkyl; and e, g, x and y represent CRm or N+Rk, with Rk as defined above and Rm representing hydrogen. Within this subset, all other variables are as originally defined with respect to formula I.

Another more preferred subset of compounds is represented by formula Id: WO 99/20270 PCT/US98/22111 -23 HO Rrr

HO

RH H

R

H3C R

N-

0 N C0 2

M

Id

OS

0 or a pharmaceutically acceptable salt thereof, wherein: CO2M represents a carboxylate anion; one R group is attached to the naphthosultam platform which contains a positively charged moiety, and the other R group is selected from hydrogen, halo and C1-6 straight or branched chain alkyl, unsubstituted or substituted with one to four Rd groups;

R

d is as originally defined; Q is selected from the group consisting of: (CH2)b e L (CH 2 )a wherein a and b are as originally defined, and

R

x represents a member selected from the group consisting of: hydrogen or a C1-8 straight- or branched- chain alkyl, optionally interrupted by one or two of O, S, SO, SO2, NRw, N+RhRw, or said chain being unsubstituted or substituted with one to four of halo, CN, N02, ORw, SRW, SORW, S02Rw, NRhRw, N+(Rh) 2 Rw, C(O)NRhRw, S0 2 NRhRw, CO2RW, OC(O)Rw, OC(O)NRhRw, NRhC(O)Rw, NRhC(O)NRhRw, phenyl or heteroaryl, said phenyl and heteroaryl group being optionally substituted with from one to four R i groups or with one to two C1-3 straightor branched- chain alkyl groups, said alkyl groups being unsubstituted or substituted with one to four R i groups; WO 99/20270 PCT/US98/22111 -24 Rh represents hydrogen or a C1-6 straight or branched chain alkyl group;

R

W is as originally defined; R* is selected from: 11 and d d'y eg wherein d represents NRk; Rk represents -Ci-6 straight or branched chain alkyl; and e, g, x and y represent CRm or N+Rk, with R k as defined above and R m representing hydrogen. Within this subset, all other variables are as originally defined with respect to formula I.

Still more preferably, the present invention relates to a compound represented by formula Ia wherein the R group at position 4 represents a positively charged moiety, and the R groups at position 3 and 5 represent hydrogen.

In particular, such compounds can be represented by formula Ie:

HO

H H H

R

H3C O N

CO

2 o Ie O 0 or a pharmaceutically acceptable salt thereof, wherein: R contains a positively charged moiety selected from the group consisting of: Q, and a C1-6 straight or branched alkyl chain substituted with one Rd group; Rd is independently selected or Q; Q is selected from the group consisting of: WO 99/20270 PCT/US98/22111

(CH

2 )b and O L (CH 2 )a wherein a and b are as originally defined, and Rx represents a member selected from the group consisting of: hydrogen or a C1-8 straight- or branched- chain alkyl, optionally interrupted by one or two of O, S, SO, S02, NRW, N+RhRw, or said chain being unsubstituted or substituted with one to four of halo, CN, N02, ORW, SRw, SORW, SO2R w NRhRW, N+(Rh) 2 RW, C(0)NRhRw, SO2NRhRw, CO2R w OC(O)Rw, OC(0)NRhRw, NRhC(0)RW, NRhC(0)NRhRw, phenyl or heteroaryl, said phenyl and heteroaryl group being optionally substituted with from one to four Ri groups or with one to two C1-3 straight or branched chain alkyl groups, said alkyl groups being unsubstituted or substituted with one to four Ri groups; R* is selected from: 1el1 and d-y e wherein d represents NRk; Rk represents -C1- 6 straight or branched chain alkyl; and e, g, x and y represent CRm or N+Rk, with Rk as defined above and Rm representing hydrogen.

Likewise, such compounds can be represented by formula If: WO 99/20270 PCT/US98/22111 -26 HO Rrr R H H

H

3

C

O N C0 2 If O0 0 or a pharmaceutically acceptable salt thereof, wherein: R contains a positively charged moiety selected from the group consisting of: Q, and a C1-6 straight or branched alkyl chain substituted with one Rd group; Rd is independently selected or Q; Q is selected from the group consisting of: (CH2)b n N and \N-Rx L (CH 2 )a wherein a and b are as originally defined, and Rx represents a member selected from the group consisting of: hydrogen or a CI-8 straight- or branched- chain alkyl, optionally interrupted by one or two of O, S, SO, SO2, NRw, N+RhRw, or said chain being unsubstituted or substituted with one to four of halo, CN, N02, ORw, SRw, SORW, SO2RW, NRhRw, N+(Rh) 2 Rw, C(O)NRhRw, SO 2 NRhRw, CO2Rw, OC(O)Rw, OC(O)NRhRw, NRhC(O)Rw, NRhC(0)NRhRw, phenyl or heteroaryl, said phenyl and heteroaryl group being optionally substituted with from one to four R i groups or with one to two C1-3 straight or branched chain alkyl groups, said alkyl groups being unsubstituted or substituted with one to four R i groups; R* is selected from: WO 99/20270 PCT/US98/22111 -27 I Iand x d d-y e.

wherein d represents NRk; Rk represents -C1-6 straight or branched chain alkyl; and e, g, x and y represent CR m or N+Rk, with Rk as defined above and Rm representing hydrogen.

A still more preferred subset of compounds of the invention is represented by formula Ie wherein: R represents

(CH

2 )b I -(CH2)I1-6-N-.O N- R x L (CH 2 )a and Rx, a, b and L- are as originally defined.

Another more preferred subset of compounds of the invention is represented by formula Ig: rr

HO

H H

H

3

C

N

CO

2 M IgC2 0 wherein: R represents

(CH

2 )b I -(CH2)1-6-NON- R x 20 L (CH L (OH 2 )a WO 99/20270 PCT/US98/22111 -28 and Rx, a, b and L- are as originally defined.

Another more preferred subset of compounds of the invention are presented by formula Ih:

P

HH

H

3 (R) 3 0 C0 2 M Ih wherein: X represents CH 2 CHR, C=CHR, O, S, SO, SO2, CO,

CO

2 OCO, NR; CO2M represents a carboxylate anion; Rd is as originally defined; Rh represents hydrogen or a Ci-6 straight or branched chain alkyl group; Q is selected from the group consisting of: (CH2)b and NO(D N- R e L (CH 2 )a wherein a and b are as originally defined, and Rx represents a member selected from the group consisting of: hydrogen or a C1-8 straight- or branched- chain alkyl, optionally interrupted by one or two of O, S, SO, S02, NRw, N+RhRW, or said chain being unsubstituted or substituted with one to four of halo, CN, NO2, ORw, SRw, SORw, SO2RW, NRhRw, N+(Rh) 2 RW, C(0)NRhRw, SO 2 NRhRw, CO2R w OC(O)Rw, OC(O)NRhRw, NRhC(O)Rw, NRhC(O)NRhRw, phenyl WO 99/20270 PCT/US98/22111 -29 or heteroaryl, said phenyl and heteroaryl group being optionally substituted with from one to four Ri groups or with one to two C1-3 straight- or branched- chain alkyl groups, said alkyl groups being unsubstituted or substituted with one to four R i groups; R* is selected from: S I and d d'y e wherein d represents NRk; Rk represents -C1-6 straight or branched chain alkyl; and e, g, x and y represent CRm or N+Rk, with Rk as defined above and Rm representing hydrogen.

Within this subset, all other variables are as originally defined with respect to formula I.

Another more preferred subset of compounds of the invention are presented by formula Ii:

P

HH H

H

3

C

O N O C0 2

M

(R)

3 li CO2M represents a carboxylate anion; Rd is as originally defined; Rh represents hydrogen or a C1-6 straight or branched chain alkyl group; Q is selected from the group consisting of: WO 99/20270 PCT/US98/22111

(CH

2 )b a and N L (CH 2 )a wherein a and b are as originally defined, and Rx represents a member selected from the group consisting of: hydrogen or a C1-8 straight- or branched- chain alkyl, optionally interrupted by one or two of O, S, SO, S02, NRw, N+RhRw, or said chain being unsubstituted or substituted with one to four of halo, CN, N02, ORW, SRw, SORw, SO2RW, NRhRw, N+(Rh) 2 Rw, C(O)NRhRw, S02NRhRw, CO2Rw, OC(O)RW, OC(O)NRhRw, NRhC(O)Rw, NRhC(0)NRhRw, phenyl or heteroaryl, said phenyl and heteroaryl group being optionally substituted with from one to four R i groups or with one to two C1-3 straight- or branched- chain alkyl groups, said alkyl groups being unsubstituted or substituted with one to four R i groups; R* is selected from: x d e "I and d<y /9 d-Y eg wherein d represents NRk; Rk represents -CI-6 straight or branched chain alkyl; and e, g, x and y represent CRm or N+Rk, with Rk as defined above and Rm representing hydrogen.

Within this subset, all other variables are as originally defined with respect to formula I.

Another more preferred subset of compounds of the invention are presented by formula Ij: WO 99/20270 PCT/US98/22111 -31 Rr

SHH

H

3

C

0 I (R) 3

CO

2 M S wherein: CO2M represents a carboxylate anion; Rd is as originally defined; Rh represents hydrogen or a C1 -6 straight or branched chain alkyl group; Q is selected from the group consisting of: (CH2)b N V" lN and N N-R L (CH 2 )a wherein a and b are as originally defined, and Rx represents a member selected from the group consisting of: hydrogen or a C1-8 straight- or branched- chain alkyl, optionally interrupted by one or two of O, S, SO, SO2, NRw, N+RhRw, or said chain being unsubstituted or substituted with one to four of halo, CN, NO2, ORw, SRW, SORW, SO2Rw, NRhRw, N+(Rh) 2 RW, C(O)NRhRw, SO 2 NRhRw, CO2R

W

OC(O)RW, OC(O)NRhRw, NRhC(O)Rw, NRhC(O)NRhRW, phenyl or heteroaryl, said phenyl and heteroaryl group being optionally substituted with from one to four R i groups or with one to two C1-3 straight- or branched- chain alkyl groups, said alkyl groups being unsubstituted or substituted with one to four R i groups; R* is selected from: i andI wherein d represents NRk; Rk represents -Ci1 -6 straight or branched chain alkyl; and e, g, x and y represent GRin or N+Rk, with Rk as defined above and Rm representing hydrogen.

Within this subset, all other variables are as originally defined with respect to formula I.

Representative examples of compounds of the invention are shown below. The invention is intended, where appropriate, to include protonated amines protonated at the appropriate pH, pH 7.

Rep resentative Examples :V e: H

L

H

3 0~ N'4 H C02 oz and 20E-1 0

HOHO

H

H

3 C

N~

*N'

0 C0 **S 25 .O 0 E-2 HHH

HOH

HH

3

H

N'C

H

3

C

0 N0 2

N~\

E-3 I i E-4 U Me [RALIBAA]08619.doc:ACR WO 99/20270 WO 9920270PCTIUS98/221 11 33

H

3

C

H

3

C

C0 2 o0 0 C0 2 0

S:

E-6 0

H

3 0 C020 WO 99/20270 PCTIUS98/22111 34 Table

Q

PhS OH

F

9 0 10 Nd PNe Ph phenyl

F

9

H

H

2 N N 0d

N

-h

H

2 N y0

N;

p2)

H

3 C, H

N'

r-

N+

L-47

H

3 C, N- CH 3 rj o N (q7 ?H3

CS

N C H 3

NS

Lh C H 3 S=0

N+

L-A-

WO 99/20270 WO 9920270PCT/US98/221 11 35 9 9

H

21 22 S0 23(N

N-

Lh-

NH

2 H 2 N I(II1aNH 24 N+ 25 N 26 6 e9[N9 WO 99/20270PCUS/211 PCTIUS98/221 11 -36

HOH

H

3 0 0~ N 002 0 0

NH

2

HO

r-1--o .OH 3 34 N 35N 36

N

0 N0 NH

HO

0

N

4 2 WO 99/20270 WO 9920270PCTfUS98/221 11 37-

HO

H

H

4

H

3

C

0

N

C02 oz Table 0i

Q

#Q#Q

#Q

OH

,O H 3 42 43 C N.,f

N.,

HO

H H

H

3

C

N!

0 C 02 0 S IQ 0

TABLE

NH

2

HO

r 46+ 47 H3 WO 99/20270 WO 9920270PCTJUS98/221 11 -38

H

H

3 C -T r

NH

2 c- iJ N

HO

N

F

N Table

Q

C H 3

Q

OH

s N L-h WO 99/20270 WO 9920270PCTIUS98/221 11 39 1- 3

C

Q

NH2 r o N

S

N+

HO

N

N

Table

Q

NH

2

L-

HO

N+

F

t-4- WO 99/20270 WO 9920270PCTIUS98/22111I 40

TABLE

-1 U-

PH

3

OH

N.

WO 99/20270 WO 9920270PCT/US98/221 II -41

H

3

C

1T

Q

NH

2 0~

HO

N+

C H3 1)

H

3

C

TABLE

Q

.CH

3 ,4,

OH

'C>

Nh WO 99/20270 WO 9920270PCT/US98/221 11 42 HO

Q

H H 1- 3

C

0 N!

N

002 QOS Table 0 #1 QQ

NH

2 HO

CH

78 N 79 N+(1 N

N.,

144 4

HO

H H

H

3 C N0 2 00

TABLE

WO 99/20270 WO 9920270PCT/US98/221 11 -43 ____Table #2 Q

Q

NH

2 HO

/CH

3 86 ~N 8 7 N 88 r

TABLE

WO 99/20270 WO 9920270PCTIUS98/221 11 44

CO

2

QO:S*

0

B

2

NH

2 C3

NH

2

N+

S

L!h

Q

NH

2

N+

L-7

OH

3

HO

N+

CH

3

HO

N+

BZ

OH

3

NH

2 >-L0

N+

HO

N+

OH

3

HO

N+

u+) wherein Q is as defined in the tables and Lpharmaceutically acceptable counterion.

represents a WO 99/20270 WO 9920270PCT/US98/221 II HO HO H

H

H

3 C H 3

C

NO

\CON H 2 HO HHHO H H H H j

H

3 C H 3

C

0 0 (D C 0 2 /0 C0 2 L+ 0 0 No

CONH

2 WO 99/20270 WO 9920270PCT/US98/221 11 -46 HOH H H H 4.H 3 0 H 3

C

N N 0 -N 0LN

CONH

2 H HH H H

H

3 C H 3 0 N- C0- C0 2-50 N s

CONH

2

HO

H L H HH

H

3 C H A

H-

3

CN

N 00 0

G

NN

N /~\®CONH 2 HO H HH H OH HHH I-i~CH 3

C

N 0 e N 0 LE

NH

2 L iCON -N (E ONH WO 99/20270 PCTIUS98/22111I -47

H

H

3 C WO 99/20270 PCTIUS98/221 11 -48

HOH

H H H3C

N!

00 0 0

HO

jHH

H

3

C

0 CO2Na e CONH2 H H

H

3 C0N H NHH

HO

H0

L

N'2 COP HO® CONH2 H,,C yI 6- N

N

0 CO2P

NH

2 L 0?

HHN

H

3 CO

N'

0 C0e WO 99/20270 PCTIUS98/221 11 -49- ,H H HO HH

H

3 C N

H

3

C

NIN N 0 C02Na s C02® SNLN

CONH,

NH

2 HO CONH 2

HO

NH 0)H H

H

3 C H 3

CN

N/ N N' L' represents a positively charged counterion, e.g. Na', or an appropriate molar amount of a divalent cation, Ca" 2 The compounds of the present invention are prepared by two basic processes which are illustrated by the following generic schemes: General Synthesis Scheme I

OAC.+

TMSOTf OP. CICOCO2CH 2

CH=CH

2 OP, Et3N, CH2CI 2 0 (EIO)3P, heat 0 0 03.) P P H HP H H N/ 1)I-HC0 2 H

N

OH Ph3P, DIAD N/ OH Ph3P, DIAD N U 00 THF,OC 0o THF, 0 0 C 00 02) Base Mitsunobu Reaction Deprotections N UC 0 rn C02M WO 99/20270 PCT/US98/22111 General Synthesis Scheme 2 1 NUC: P 1N.) CICOCO2CH 2 CH=CH2 "0 Oxidation (E0)3P,heat 0 Deprotect O P

P

\UC Deprotections

C

0 CO2M In words relative to Scheme 1, the tricyclic synthon is prepared in a similar fashion to the description found in EPO 507,313, in which the acetoxyazetidinone, wherein P is F or a suitably protected hydroxyl radical, such a allyloxycarbonyl, t-butyldimethylsilyl (TBS), tbutyldiphenylsilyl (DPTBS) or the like, is reacted with a suitably protected 2-hydroxy-cyclohexanone derivative such a trimethysilyl (TMS) or t-butyldimethylsilyl, or the like, using the conditions of Barrett, etal. A. G. M. Barrett, etal, J. Org. Chem., 1984, 49, 1679.) to effect displacement to provide a mixture of azetidinones in which the desired beta-isomers can be separated. Conversion to the oxalamide intermediate is accomplished with chloroallyloxalate or the like, and triethylamine in methylene chloride solution at from -780C to 0oC, which in turn is converted to the trinem synthon by in situ formation of the trisubstituted phosphorane intermediate with excess triethylphosphite, or diethylmethylphosphonite, or the like in toluene, p-xylene, or mesitylene, or the like at temperature of from 1200C to 1600C and concommitant intramolecular cyclization on prolonged heating at the same temperature range. Desilylation of either TMS or TBS covering groups using tetrabutylammonium fluoride TBAF or ammonium bifluoride and acetic acid in tetrahydrofuran THF solvent at a temperature of from 0OC to 500C, provides the requisite alcohol.

The configuration of the hydroxyl group is inverted prior to incorporation of the MRS active sidechain, using the Mitsunobu reaction partners with anhydrous formic acid, or the like, to produce the formate WO 99/20270 PCT/US98/22111 -51 ester, or the like, of the opposite configuration as the starting alcohol.

Hydrolysis of the formate ester or the like provides the alcohol of the opposite configuration ready for incorporation of the MRS pharmacophore to ultimately provide the trinems of the invention in their protected form. Through the intermediacy of the Mitsunobu reaction for a review see: Hughes, D.L. Organic Reactions, Paquette, L. ed., Vol. 42, John Wiley Sons, USA, 1992.), nucleophilic (NUC:) side chains (naphthosultams, phenols, and mercaptobenzothiazoles) in combination with reagents that comprise the Mitsunobu reaction such as an azodicarboxylate like diethylazodicarboxylate

(DEAD),

diisopropyldiazodicarboxylate(DIAD), and tetramethyldiazodicarboxamide (TMAD), or the like, and a trisubstituted phosphine, such as triphenylphosphine, tri-n-butylphosphine, and the like, in a suitable solvent such as tetrahydrofuran (THF), ether, acetonitrile, dimethylformamide (DMF), benzene, dimethylsulfoxide (DMSO), and the like at a temperature between about -20 °C and 35 °C for about 5 to 90 minutes can be readily incorporated onto the trinem nucleus. The covering groups of the resulting new trinems are then removed in accordance with the previous definitions of P. Typically, when P is a silyl based protecting group for the hydroxyl radical, the deprotections are performed sequentially: first, desilylation with TBAF/HOAc or aqueous triflic acid in THF, or the like; and second, deallylation using the palladium catalyzed method of Jeffrey and McCombie (JOC, 1982, 47, 587.) Alternatively, if the hydroxyl protecting is allylcarbonyl, then the deprotections are performed simultaneously by the latter method.

Alternatively, as depicted in Scheme 2, the cyclohexeneepoxy-azetidinone, as described in EP 416,953 and incorporated by reference herein, is reacted with the previously defined nucleophiles (NUC:) of the invention in the presence of a base in a manner as described in EP 416,953. The resulting alcohol is oxidized to the ketone via a Swern oxidation or the like, and after the removal of the azetidinone protecting group, if it was necessary, the resulting azetidinone is then processed in a fashion analogous to that outlined in WO 99/20270 PCT/US98/22111 -52 Scheme 1, ie, oxalamide and ylid formation followed by cyclization provides the fully elaborated trinems ready for the deprotection sequences.

In most instances, the aforementioned nucleophilic partners in the Mitsunobu reaction possess functionalized substituents which allow for the introduction of the previously defined heterocycles, Q, and thereby necessitate additional chemical steps in the general synthesis plan. These steps are outlined in Scheme 3. Once the fully elaborated trinem has been synthesized, the substitutent tether from the particular side-chain class typically possesses a silyl covered hydroxyl radical which in the first step is then uncovered in the usual way as expressed above. Next the hydroxyl group is converted to a suitable leaving group such as a triflate, mesylate, tosylate, iodide, chloride, bromide, and the like, and then displacing the resulting leaving group with a compound Q, such as N-methyl-imidazole, N-(2-hydroxyethyl)-imidazole,

N-

methyl-diazabicyclooctane, 1-(carbamoylmethyl)-4-aza- 1-azoniabicyclo-[2.2.2.2.]-octane, 1-(3-hydroxyprop-1-yl)-4-aza-1azoniabicyclo-[2.2.2.]-octane, pyridine, morpholine and the like which contain a nitrogen atom that can act as a nucleophile. Alternatively, in some cases, the charged substituent may be incorporated in the side chain before addition to the trinem or may be introduced after the final deprotections. However, introduction of the charged substituent by modification of the hydroxyl group before deprotection is greatly preferred.

WO 99/20270 PCT/US98/2211 -53 General Synthesis Scheme 3 P p SDesilylation UC Activation NUC 'Nv'vOSI N :NUC ,OH 0 0 0 0 P p N/ I Displacement, Q Depro ections 0y NUC 0 NUC -0,.Q

P

eo The conversion of the hydroxyl group to a suitable leaving group is accomplished by treating the hydroxyl substituted compound in a suitable solvent such as dichloromethane, tetrahydrofuran, ether, benzene, and the like with an activating reagent, such O O Go The conversion of the hydroxyl group to a suitable leaving group is accomplished by treating the hydroxyl substituted compound in a suitable solvent such as dichloromethane, tetrahydrofuran, ether, benzene, and the like with an activating reagent, such as trifluoromethanesulfonic anhydride, methanesulfonic anhydride, toluenesulfonic anhydride, methanesulfonyl chloride, benzenesulfonyl chloride, toluenesulfonyl chloride, and the like in the presence of a suitable base such as triethylamine, tributylamine, diisopropylethylamine, and the like at a temperature between about -100 0 C and 0°C for about 5 to 120 minutes. is treated with 1-3 molar equivalents of compound Q at a temperature between about -78 0 C and 50 0 C for about to 120 minutes.

The intermediate thus obtained contains a leaving group, which may be converted to an alternative leaving group, iodide, by treating a solution of the intermediate in a suitable solvent such as acetone, methyl ethyl ketone, and the like at about -10 0 C to 50 0 C with an excess of sodium iodide or potassium iodide for about 0.25 to 24 hours.

WO 99/20270 PCT/US98/2211 -54 In many cases, the iodide is obtained in sufficiently pure form that it may be used without further purification. For ease of handling, the iodide, if not crystalline, may be lyophilized from benzene to afford an amorphous, easily handled, solid.

The activated hydroxyl group or iodide is displaced by reacting with 1-3 molar equivalents of compound Q at a temperature between about -78 0 C and 50°C for about 15 to 120 minutes, in a solvent such as acetonitrile, dichloromethane, DMF, or DMSO, or the like.

In some cases, it is desirable to form the activated intermediate in one solvent, isolate the activated intermediate, and conduct the displacement reaction in a different solvent. In other cases, the displacement may be conducted without isolation of the intermediate and, in cases where Q is also used as a base, may even be concurrent with the formation of the activated intermediate.

In cases where the displacement reaction is best accomplished by using the iodide, a solution of the iodide is combined with an approximately equivalent amount (0.9 1.05 molar equivalents) of compound Q. A silver salt of a non-nucleophilic acid, such as silver trifluoromethanesulfonate, silver tetrafluoroborate and the like is then added. Although the reaction will proceed in the absence of the silver salt, the reaction proceeds more rapidly in the presence of the silver salt. In addition, the silver salt assists in the removal of the displaced iodide from the reaction mixture which can improve the efficiency of subsequent steps. The resulting mixture is then subjected to a standard work-up procedure familiar to those skilled in the art to afford a crude product which is purified, if necessary, by recrystallization or chromatography.

An alternative method for introducing a positive charge into the side chain may be applied to side chains Rsc groups) that contain a nitrogen atom which may be quaternized by reaction with a suitable alkylating reagent AR, such as methyl iodide, methyl bromide, benzyl trichloroacetimidate, methyl trifluoromethanesulfonate, triethyloxonium tetrafluoroborate, and the like. Quaternization of the nitrogen atom in the side chain is effected by treating a solution of the WO 99/20270 PCT/US98/22 11 compound with a slight excess (1.05 to 1.2 molar equivalents) of the alkylating reagent.

The synthesis of the target compound is completed by removing any protecting groups which are present in the penultimate intermediate using standard techniques which are well known to those skilled in the art. The deprotected final product is then purified, as necessary, using standard techniques such as ion exchange chromatography, HPLC on reverse phase silica gel, MPLC on reverse phase polystyrene gel, and the like or by recrystallization.

The final product may be characterized structurally by standard techniques such as NMR, IR, MS, and UV. For ease of handling, the final product, if not crystalline, may be lyophilized from water to afford an amorphous, easily handled solid.

The naphthosultam, 2-mercapto-benzothiazole, and phenolic side chain groups used in the synthesis of the compounds of the present invention have, in some cases, been described in the chemical literature.

In particular the 2-mercapto-benzothiazoles have been adequately described in US 5,496,816, issued March 5, 1996, which is incorporated herein by reference. In other cases, precursor compounds which may be readily converted to the requisite side chain types have been described in the literature. In cases where the requisite synthons are unknown in the literature it is necessary to synthesize them by a newly developed synthesis. One skilled in the art can adapt a previously published synthesis of an analogous synthon to prepare the requisite compound in a straightforward manner without undue experimentation. Numerous examples of these syntheses are described herein (see below).

The compounds of the present invention are valuable antibacterial agents active against various Gram-positive and to a lesser extent Gram-negative bacteria, and accordingly find utility in human and veterinary medicine.

Many of compounds of the present invention are biologically active against MRSA/MRCNS. In vitro antibacterial activity is predictive of in vivo activity when the compounds are WO 99/20270 PCT/US98/22111 -56 administered to a mammal infected with a susceptible bacterial organism.

Using standard susceptibility tests, the compounds of the invention are determined to be active against MRSA.

The compounds of the invention can be formulated in pharmaceutical compositions by combining the compound with a pharmaceutically acceptable carrier. Examples of such carriers are set forth below.

The compounds may be employed in powder or crystalline form, in liquid solution, or in suspension. They may be administered by a variety of means; those of principal interest include: topically, orally and parenterally by injection (intravenously or intramuscularly).

Compositions for injection, a preferred route of delivery, may be prepared in unit dosage form in ampules, or in multidose containers. The injectable compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain various formulating agents. Alternatively, the active ingredient may be in powder (lyophillized or nonlyophillized) form for reconstitution at the time of delivery with a suitable vehicle, such as sterile water. In injectable compositions, the carrier is typically comprised of sterile water, saline or another injectable liquid, peanut oil for intramuscular injections. Also, various buffering agents, preservatives and the like can be included.

Topical applications may be formulated in carriers such as hydrophobic or hydrophilic bases to form ointments, creams, lotions, in aqueous, oleaginous or alcoholic liquids to form paints or in dry diluents to form powders.

Oral compositions may take such forms as tablets, capsules, oral suspensions and oral solutions. The oral composions may utilize carriers such as conventional formulating agents, and may include sustained release properties as well as rapid delivery forms.

WO 99/20270 PCTIUS98/22111 -57 The dosage to be administered depends to a large extent upon the condition and size of the subject being treated, the route and frequency of administration, the sensitivity of the pathogen to the particular compound selected, the virulence of the infection and other factors. Such matters, however, are left to the routine discretion of the physician according to principles of treatment well known in the antibacterial arts. Another factor influencing the precise dosage regimen, apart from the nature of the infection and peculiar identity of the individual being treated, is the molecular weight of the compound.

The compositions for human delivery per unit dosage, whether liquid or solid, may contain from about 0.01% to as high as about 99% of active material, the preferred range being from about 10-60%. The composition will generally contain from about 15 mg to about 2.5 g of the active ingredient; however, in general, it is preferable to employ dosage amounts in the range of from about 250 mg to 1000 mg. In parenteral administration, the unit dosage will typically include the pure compound in sterile water solution or in the form of a soluble powder intended for solution, which can be adjusted to neutral pH and isotonic.

The invention described herein also includes a method of treating a bacterial infection in a mammal in need of such treatment comprising administering to said mammal a compound of formula I in an amount effective to treat said infection.

The preferred methods of administration of the Formula I antibacterial compounds include oral and parenteral, i.v.

infusion, i.v. bolus and i.m. injection.

For adults, about 5-50 mg of Formula I antibacterial compound per kg of body weight given one to four times daily is preferred. The preferred dosage is 250 mg to 1000 mg of the antibacterial given one to four times per day. More specifically, for mild infections a dose of about 250 mg two or three times daily is recommended. For moderate infections against highly susceptible gram positive organisms a dose of about 500 mg three or four times WO 99/20270 PCT/US98/22111 -58 daily is recommended. For severe, life-threatening infections against organisms at the upper limits of sensitivity to.the antibiotic, a dose of about 1000-2000 mg three to four times daily may be recommended.

For children, a dose of about 5-25 mg/kg of body weight given 2, 3, or 4 times per day is preferred; a dose of mg/kg is typically recommended.

The compounds of Formula I are of the broad class known as carbapenems. Many carbapenems are susceptible to attack by a renal enzyme known as dehydropeptidase (DHP). This attack or degradation may reduce the efficacy of the carbapenem antibacterial agent. Many of the compounds of the present invention, on the other hand, are less subject to such attack, and therefore may not require the use of a DHP inhibitor. However, such use is optional and contemplated to be part of the present invention. Inhibitors of DHP and their use with carbapenems are disclosed in, e.g.,[European Patent Application Nos. 79102616.4, filed July 24, 1979 (Patent No.

0 007 614); and 82107174.3, filed August 9, 1982 (Publication No.

0 072 014)].

The compounds of the present invention may, where DHP inhibition is desired or necessary, be combined or used with the appropriate DHP inhibitor as described in the aforesaid patents and published application. The cited European Patent Applications define the procedure for determining DHP susceptibility of the present carbapenems and disclose suitable inhibitors, combination compositions and methods of treatment. A preferred weight ratio of Formula I compound: DHP inhibitor in the combination compositions is about 1:1.

A preferred DHP inhibitor is 7-(L-2-amino-2-carboxyethylthio)-2-( 2 ,2-dimethylcyclopropanecarboxamide)-2-heptenoic acid or a useful salt thereof.

The invention is further described in connection with the following non-limiting examples.

WO 99/20270 PCT/US98/22111 -59 PREPARATIVE EXAMPLE 1 SYNTHESIS OF 5-(TRIMETHYLSILYLOXYMETHYL)-1.8-

NAPHTHOSULTAM

OH

O(TMS)

Br Br2 BuLi 12 HCHO

BSA

STHF

THF

5510 45/ silica gel N- o HN-- SO H N-SO ,N-S HI H H HN%% 0 0 0 0 Step 1: 5-Bromo-1.8-naphthosultam A suspension of 1,8-naphthosultam (5 g, 24.4 mmol) in acetic acid (20 mL) was treated with a dark solution of iodine (6.5 g, 25.6 mmol) and bromine (1.3 mL, 25.2 mmol) in acetic acid (20 mL) over 10 minutes. The suspension was stirred an additional 95 minutes then placed in a 60°C oil bath for 30 minutes. After cooling to room temperature, the mixture was added to a 1% aqueous NaHSO 3 solution (300 mL). The dark precipitate was filtered and dried overnight under a stream of nitrogen. The resulting solid (6 g) was dissolved in ethyl acetate then silica gel (ca. 6 g) was added and the mixture was evaporated under vacuum. The silica-adsorbed mixture was loaded onto a 4.5 x 30 cm silica column (silica gel 60) and was eluted with ethyl acetate/ methylene chloride, collecting 25 mL fractions. Fractions 24-60 were combined and evaporated to give a green solid which was recrystallized from toluene to give the title compound as a light green solid (3.8 g).

IH NMR (CDC1 3 500 MHz) 5 6.82 ArH), 6.83 (br.s, NH), 7.80 (d, ArH), 7.93 ArH), 8.05 ArH) and 8.38 ArH).

Step 2: 5-(hydroxvmethyl)-1,8-naphthosultam A solution of 5-bromo-1,8-naphthosultam (0.5 g, 1.76 mmol) in anhydrous tetrahydrofuran (10 mL) under nitrogen was cooled in a dry ice acetone bath in a three neck flask. N-butyllithium (2.75 mL of a 1.6 M solution in hexanes, 4.4 mmol) was added over WO 99/20270 PCT/US98/22111 2 minutes and the suspension was stirred an additional 7 minutes.

Paraformaldehyde (0.317 g, 10.6 mmol), placed in the bulb of a drying tube which was attached to the flask, was heated with a heat gun while a slow stream of nitrogen was blown over the solid. The generated formaldehyde was carried into the flask and the carrier gas vented through a line connected to a Firestone valve over a period of 13 minutes. After an additional 5 minutes, the mixture was removed from the bath and stirred for 10 minutes. Aqueous hydrochloric acid (3 mL of a 2 N solution) was added and the clear suspension was stirred an additional 10 minutes. The mixture was partitioned between ethyl acetate (50 mL) and water (50 mL). The ethyl acetate layer was washed with saturated aqueous sodium chloride (20 mL), dried over magnesium sulfate, filtered, and evaporated. The solid residue (0.5 g) was dissolved in 5% methanol/ methylene chloride and was loaded onto a 24 x 4.5 cm silica gel column (silica gel 60, packed/ loaded/ eluted with methanol/ methylene chloride), collecting 8 mL fractions. Fractions 12-42 were combined and evaporated to give the title compound as a white solid (0.185 g).

IH NMR (DMSO-d 6 500 MHz) 6 4.85 2OH), 5.22 ICH 2

OH),

6.82 ArH), 7.52 ArH), 7.83 ArH), 8.13 ArH) and 8.38 (d, ArH).

Step 3: 5-(trimethylsilvloxvmethyl)-1.8-naphthosultam A solution of 5-(hydroxymethyl)-l,8-naphthosultam (0.185 g, 0.79 mmol) in tetrahydrofuran (1 mL) was treated with N,O- Bis(trimethylsilyl)acetamide 0.49 mL, 1.98 mmol). The mixture was stirred at room temperature for 1 hour then evaporated.

The residual oil was dissolved in methylene chloride (1 mL) and was filtered through silica gel 60 (2.5 eluting the silica with additional methylene chloride (50 mL). The solvent was evaporated under vacuum and the residue was lyophilized from benzene (3 mL) to give the title compound as a white solid (0.20 g).

WO 99/20270 PCT/US98/22111 -61 IH NMR (CDCl3, 500 MHz) 6 0.19 SiMe 3 5.07 CH 2 6.83 (d, ArH), 6.87 (br.s, NH), 7.50 ArH),7.78 ArH), 7.95 ArH) and 8.26 ArH).

PREPARATIVE EXAMPLE 2 SYNTHESIS OF 5-(2-(TRIMETHYLSILYLOXY)-ETHYL)-1,8-

NAPHTHOSULTAM

OH

O(TMS)

Br BuLi S ethylene oxide

BA

F( B F(OEt) THF THF silica gel 69% HN-- O 53% ,N-S.

O

HN-S.

H' O H 0 H 0 0 0 Step 1: 5-(2-(hydroxv)-ethyl)-1,8-naphthosultam A solution of 5-bromo-1,8-naphthosultam (0.6 g, 2.11 mmol) in anhydrous tetrahydrofuran (OmL) under nitrogen was cooled in a dry ice/ acetone bath. N-butyllithium (3.3 mL of a 1.6 M solution in hexanes, 5.28 mmol) was added over 7 minutes and the suspension was stirred an additional 8 minutes. An excess of ethylene oxide was slowly bubbled into the mixture over 5 minutes. Boron trifluoride etherate (0.26 mL, 2.11 mmol) was then added over 5 minutes. After an additional 20 minutes, the reaction was quenched with the addition of acetic acid (0.35 mL, 6 mmol). The mixture was partitioned between ethyl acetate (100 mL) and water (100 mL). The ethyl acetate layer was washed with saturated aqueous sodium chloride (50 mL), dried over magnesium sulfate, filtered, and evaporated. The residual oil (0.7 g) was dissolved in 5% methanol/ methylene chloride and was loaded onto a 24 x 2.75cm silica gel column (silica gel 60, packed/ loaded/ eluted with 5% methanol/ methylene chloride), collecting 8 mL fractions.

Fractions 26-39 were combined and evaporated to give the title compound as an oil (0.28 g).

WO 99/20270 PCT/US98/22111 -62 IH NMR (DMSO-d 6 500 MHz) 8 3.22 CH 2 Ar), 3.87 c2OH), 6.79 ArH), 7.35 ArH), 7.74 ArH), 7.91 ArH) and 8.21 (d, ArH).

Step 2: 5-(2-(trimethvlsilvloxy)-ethvl)- 18-naphthosultam A solution of 5-(2-(hydroxy)-ethyl)-1,8-naphthosultam (0.09 g, 0.36 mmol) in tetrahydrofuran (1 mL) was treated with N,O- Bis(trimethylsilyl)acetamide (0.223 mL, 0.90 mmol). The mixture was stirred at room temperature for 20 minutes and was evaporated. The residual oil was dissolved in methylene chloride (3 mL) and was filtered through silica gel 60 (2.7 eluting the silica with additional methylene chloride (50 mL). The solvent was evaporated under vacuum and the residue was lyophilized from benzene (3 mL) to give the title compound as a white solid (0.08 g).

PREPARATIVE EXAMPLE 3 SYNTHESIS OF 4-(2-(TRIMETHYLSILYLOXY)-ETHYL)-1.8-

NAPHTHOSULTAM

WO 99/20270 PCT/US98/22111 63

CH

2 C0 2 Me CH 2 00 2 Me s- CIS0 3 H CC14 460/o JoE)KE

CH

2

CO

2 Me HNO3 ppt with ether SO3KO K quant. ppt S030K® CH2C02Me NO SO3H

NO

2

SO

3

H

NO

2

CH

2

CO

2 Me SO3H Fe Dilute H2SO 4 110'C 52%

CH

2 C0 2 Me POC13 100'c NH2 OPN.G 70:30 minor isomers

CH

2

CO

2 Me CH2CH2C N.S -LA

H

THF N 71% N--S N--S H II-o H' I"o O O0 )H CH2CH2OTMS

BSA

quant.

N-S

o H IIO 0 Step 1: potassium 1-(methoxvcarbonylmethvl)-4-naphthalene sulfonate A solution of methyl 1-naphthaleneacetate (1 mL, 5.77 mmol) in carbon tetrachloride (1 mL) was cooled under nitrogen in an ice bath. Chlorosulfonic acid (0.38 mL, 5.7 mmol) was added dropwise over 8 minutes. After an additional 30 minutes, the viscous mixture was removed from the bath and was stirred at room temperature for 17 hours to give a white solid. The solid was partitioned between methylene chloride (5 mL) and water (5 mL). After filtering through solka-floc, the methylene chloride layer was extracted with more water (2 x 5 mL), and the combined aqueous extracts were basified with potassium carbonate to give a precipitate. The suspension was concentrated to approximately 5 mL and was cooled in an ice bath.

The suspension was then filtered and the collected solid was washed with cold water (2 mL). The solid was dried under a stream of nitrogen to give the title compound as a white solid (0.84 g).

WO 99/20270 PCT/US98/22111 -64 'H NMR (DMSO-d 6 500 MHz) 5 3.73 OMe), 4.27 CH 2 Ar), 7.53 ArH), 7.71 ArH), 7.76 ArH), 8.06 ArH), 8.10 ArH) and 8.73 ArH).

Step 2: 1-(methoxvcarbonylmethvl)-5-nitro-4-naphthalene sulfonic acid Potassium 1-(methoxycarbonylmethyl)-4-naphthalene sulfonate (10 g, 31.4 mmol) was added portionwise over 30 minutes to nitric acid, which was cooled in a methanol ice bath to approximately -15'C. After 2 hours, the bath temperature had reached and diethyl ether (200 mL) was added to the mixture. The precipitated solid was filtered, washed with ether (100 mL) and isopropanol mL), and dried under a stream of nitrogen to give the title compound as an approximately 70:30 mixture of the 5- and 8-nitro isomers (approximately 12 g).

'H NMR (D 2 0, 500 MHz) 5 3.69 OMe), 4.30 CH 2 Ar), 7.67 (t, ArH), 7.71 ArH), 8.18 ArH), 8.29 ArH) and 8.33 ArH).

Step 3: sodium 1-(methoxycarbonylmethyl)-5-amino-4-naphthalene sulfonate 1-(methoxycarbonylmethyl)-5-nitro-4-naphthalene sulfonic acid (2 g, 6.15 mmol) was dissolved in water (20 mL), containing mL concentrated sulfuric acid, and was added dropwise over 5 minutes to a refluxing suspension of iron (4 g, 71.6 mmol) in water (100 mL).

After refluxing for one hour, the dark mixture was cooled to room temperature, made basic with sodium carbonate, and concentrated to approximately 30mL. The residual mixture was placed on a CG-161 amberchrom resin column (2.5 x 30 cm). The column was washed with water (200 mL), 10% MeCN/ H 2 0(200 mL), and 25% MeCN/ H 2 0 (400 mL), collecting 25 mL fractions. Fractions 21-28 were combined and evaporated to give the title compound as a dark solid (0.675 g).

IH NMR (D 2 0, 500 MHz) 5 3.64 OMe), 4.18 CH 2 Ar), 7.04 (d, ArH), 7.38 ArH),7.41 ArH), 7.45 ArH) and 8.22 ArH).

WO 99/20270 PCT/US98/22111 Step 4: 4-(methoxycarbonvlmethyl)-1l8-naphthosultam Sodium 1-(methoxycarbonylmethyl)-5-amino-4naphthalene sulfonate (0.675 g, 2.13 mmol) was suspended in phosphorous oxychloride (10 g, 65.2 mmol) and was refluxed for 1 hour to give a thin suspension. The mixture was cooled to room temperature and was partitioned between ethyl acetate (100 mL) and water (100 mL). The water layer was extracted with ethyl acetate mL) and the combined ethyl acetate layers were washed with saturated aqueous sodium chloride (100 mL), dried over magnesium sulfate, filtered and evaporated to give the title compound as a solid (0.55 g).

'H NMR (CDC1 3 500 MHz) 5 3.72 OMe), 4.15 CH 2 Ar), 6.86 (br s, NH), 6.97 ArH), 7.60 ArH), 7.67 ArH), 7.71 ArH) and 7.95 ArH).

Step 5: 4-(2-(hvdroxy)-ethyl)-1,8-naphthosultam A solution of 4-(methoxycarbonylmethyl)-1,8naphthosultam (0.2 g, 0.72 mmol) in tetrahydrofuran (2 mL) was cooled under nitrogen in an ice bath. Lithium aluminum hydride (1.44 mL of a 1.0 M solution in THF, 1.44 mmol) was added over 1 minute to give a light yellow suspension. After 30 minutes, water was carefully added and the mixture was partitioned between ethyl acetate (30 mL) and IN hydrochloric acid (10 mL). The aqueous layer was extracted with ethyl acetate (50 mL) and the combined ethyl acetate layers were washed with saturated aqueous sodium chloride (10 mL), dried over magnesium sulfate, filtered and evaporated. The residual solid (0.16g) was purified by preparative thin layer chromatography (2 x 1000 micron silica gel plates, developed/ eluted with 5% MeOH/CH 2

C

2 to give the title compound as a solid (0.127 g).

'H NMR (0.14 mL CDC1 3 and 0.01 mL CD30D, 500 MHz) 6 3.33 (t,

CH

2 Ar), 3.91 CH 2 OH), 6.84 ArH), 7.49 (dd, ArH), 7.59 ArH), 7.59 ArH) and 7.83 ArH).

WO 99/20270 WO 9920270PCT/US98/221 11 66 Step 6: 4-(2-(trimethyl silvylox)- ethyl)- 1, 8- naphthosultam N,O-Bistrimethylsilylacetamide (0.31 mL, 1.25 mmol) was added to a solution of 4-(2-(hydroxy)-ethyl)-1,8-naphthosultam (0.125 g, 0.50 mmol) in tetrahydrofuran (1 mL). After one hour the mixture was evaporated and the residue was dissolved in methylene chloride (2 mL) and filtered through silica gel (2.5 The silica gel was eluted with methylene chloride (50 mL), the solvent was evaporated and the residue was lyophilized from benzene (3 niL to give the title compound as an oil (0.16 g, quant.).

H NMR (CDC1 3 500 MHz) 8 0.035 TMS), 3.37 CH 2 Ar), 3.94 (t,

CH

2 6.95 ArH), 7.56 (dd, ArH), 7.64 ArH), 7.71 (d, ArH) and 7.92 ArH).

PREPARATIVE EXAMPLE 4 SYNTHESIS OF 4- TRIMETHYLSILYLOXYMETHYLj- 18-

NAPHTHOSULTAM

Br Br Br C~N IS0 3 H H N 3/-2- N s CC1 4 ppi with ether 67% S O KID N0 2 S0 3

H

NO

2 Br S0 3

H

approx. 4:1 Br SnCI2 PC N

H

2 0 NO* 340/ 52%

NH

2 SOPNa®D Br 1s 0 1) BuUl N 2) EtOCHO 18%

N-S"

H II* 0 0 o

H

H 1 0

H

NaBH4 MeOH N~ H/N- 1 0 C BSA 88% N-S WO 99/20270 PCT/US98/22111 -67 Step 1: potassium 1-bromo-4-naphthalenesulfonate A solution of 1-bromonaphthalene (19 mL, 137 mmol) in carbon tetrachloride (24 mL) was cooled in an ice bath under nitrogen.

Chlorosulfonic acid (9.1 mL, 137 mmol) was added dropwise over minutes. After an additional 5 minutes, the heavy grey suspension was removed from the ice bath and was stirred at room temperature for 16 hours to give a grey paste. The mixture was partitioned between methylene chloride (100 mL) and water (300 mL). The aqueous layer was made basic with potassium carbonate and the resulting suspension was filtered. The collected solid was washed with methylene chloride mL) and water (50 mL), and dried under vacuum to give the title compound as a white solid (30 g, 67%).

IH NMR (DMSO-d 6 500 MHz) 8 7.61 ArH), 7.65 ArH), 7.82 2ArH), 8.14 (dd, ArH), and 8.90 (dd, ArH).

Step 2: 1-bromo-5-nitro-4-naphthalene sulfonic acid Potassium 1-bromo-4-naphthalenesulfonate (1.38 g, 4.24 mmol) was added portionwise over 20 minutes to 90% nitric acid (2 mL), which was cooled in a methanol/ ice bath to approximately After 1.5 hours, the mixture was placed in a refrigerator for 20 hours.

Diethyl ether (20 mL) was added and the precipitated solid was filtered, washed with ether (100 mL) and isopropanol (20 mL), and dried under a stream of nitrogen to give the title compound as an approximately 4:1 mixture of the 5- and 8-nitro isomers (1.25 g).

IH NMR (D 2 0, 500 MHz) 8 7.70 (dd, ArH), 8.09 ArH), 8.20 (d, ArH), 8.21 (dd, ArH), and 8.63 ArH).

Step 3: sodium 1-bromo-5-amino-4-naphthalenesulfonate 1-Bromo-5-nitro-4-naphthalenesulfonate (1 g, 3.01 mmol) and tin chloride dihydrate (1.83 g, 8.1 mmol) were suspended in a mixture of water (10 mL) and ethanol (10 mL). The resulting mixture was heated for 3 hours in a 100 °C oil bath. The mixture was cooled to room temperature and filtered. The collected solid was suspended in water (20 mL) and the mixture was made basic with sodium carbonate WO 99/20270 PCT/US98/22111 -68 then placed on a CG-161 amberchrom resin column (3 x 9 cm). The column was washed with water (300 mL) and was eluted with MeCN/ H 2 0, collecting 12 mL fractions. Fractions 17-19 were combined and evaporated to give the title compound as a solid (0.33 g).

'H NMR (D 2 0, 500 MHz) 5 7.07 (dd, ArH), 7.49 ArH), 7.83 (d, ArH), 7.85 (dd ArH) and 8.08 ArH).

Step 4: 4 -bromo-1.8-naphthosultam Sodium 1-bromo-5-amino-4-naphthalenesulfonate (1.2 g, 3.70 mmol) was suspended in phosphorous oxychloride (10 mL, 107 mmol) and the mixture was refluxed for 1 hour to give a thin suspension. The mixture was cooled to room temperature and was added to ice (100 mL). The precipitate was collected and washed with water (20 mL) then dried under vacuum (0.675 A second crop was obtained from the filtrate (0.186 The combined solids were dissolved in 5% methanol in methylene chloride and were placed on a silica gel column (29 x 3.5cm, packed and eluted with 5% methanol in methylene chloride), collecting 8 mL fractions. Fractions 27-39 were combined and evaporated to give the title compound as a solid (0.55 g).

'H NMR (0.14mLCDCl 3 and 0.OlmL CD30D, 500 MHz) 5 6.89 (d, ArH), 7.58(dd ArH),7.68 ArH), 7.73 ArH) and 7.95 ArH).

Step 5: 4-formyl-l,.8-naphthosultam A solution of 4-bromo-l,8-naphthosultam (0.24 g, 0.845 mmol) in anhydrous tetrahydrofuran (5 mL) was cooled in a dry ice/ acetone bath under nitrogen. n-Butyllithium (1.32 mL of a 1.6 M solution in hexanes, 2.11 mmol) was added and the mixture was stirred for 5 minutes. Ethyl formate (1 mL, 12.4 mmol) was then added, and after an additional 5 minutes, 2N aqueous hydrochloric acid (3 mL) was added. The flask was removed from the bath and the yellow solution was partitioned between ethyl acetate (30 mL) and water (30 mL). The ethyl acetate layer was washed with saturated aqueous sodium chloride (20 mL), dried over magnesium sulfate, filtered, and evaporated. The residual oil was purified on preparative silica gel WO 99/20270 PCT/US98/22111 -69 plates (3 x 1000 micron/ developed and eluted with 5% methanol/ methylene chloride) to give the title compound as a red solid (0.035 g).

1 H NMR (CDC13, 500 MHz) 8 7.09 ArH), 7.78 (dd, ArH), 8.12 (d, ArH), 8.30(d, ArH), 8.70 ArH) and 10.5 CHO).

Step 6: 4-(hvdroxvmethvl)-1,8-naphthosultam A solution of 4-formyl-1,8-naphthosultam (0.035 g, 0.15 mmol) in anhydrous methanol (1 mL) was cooled in an ice bath under nitrogen. Sodium borohydride (0.011 g, 0.3 mmol) was added and the solution was stirred for 30 minutes. The mixture was partitioned between methylene chloride (10 mL) and 0.2N aqueous hydrochloric acid (10 mL). The aqueous layer was extracted with 5% methanol in methylene chloride (2 x 10 mL), and the combined organic layers were evaporated to give the title compound as a yellow solid (0.032 g).

1 H NMR (0.14mLCDC13and 0.OlmL CD 3 0D, 500 MHz) 5 5.13 (s,

CH

2 OH), 6.85 ArH), 7.50 (dd, ArH), 7.57 ArH), 7.82 ArH) and 7.88 ArH).

Step 7: 4-(trimethvlsilyloxvmethvl)-l.8-naphthosultam A solution of 4-(hydroxymethyl)-1,8-naphthosultam (0.032 g, 0.136 mmol) in tetrahydrofuran (0.5 mL) was treated with N,O-Bis(trimethylsilyl)acetamide (0.084 mL, 0.34 mmol). The mixture was stirred at room temperature for 45 minutes and was evaporated.

The residual oil was dissolved in methylene chloride (1 mL) and was filtered through silica gel 60 (1 eluting the silica with additional methylene chloride (50 mL). The solvent was evaporated under vacuum and the residue was lyophilized from benzene (3 mL) to give the title compound as a white solid (0.037 g).

1 H NMR (CDC1 3 500 MHz) 5 0.23 SiMe 3 6.78 (brs, NH), 5.23 (s,

CH

2 6.97 ArH), 7.58 (dd, ArH), 7.64 ArH), 7.90 ArH) and 7.97 ArH).

WO 99/20270 WO 9920270PCTIUS98/221 11 PREPARATIVE EXAMPLE SYNTHESIS OF 4-(3 -TRIMETHYLSILYLOXYPROP- 1-YL)-I 18-

NAPHITHOSULTAM

I

CH

2

CH

2

CO

2 M e 6 steps; see -Prep. Ex. 3 Nq-S H'

O~

Steps 1-6 Synthesis of 4 -(3-trimethylsilyloxvprop-1-vl)-l.8naphthosultamn By substitution of methyl 1-naphthalenepropionate for methyl 1-naphthaleneacetate in the procedure of Preparative Example 3, 4- (3-trimethylsilyloxyprop- 1-yl)- 1,8-naphthosultam is prepared.

PREPARATIVE EXAMPLE 6.

SYNTHESIS OF 1-HYDROXYDIBENZOTHIOPHENE Step A: A stirred mixture of 3-methoxy benzenethiol (0.5 g, 3.6 mmoles), 1fluoro-2-nitrobenzene (0.5 g, 3.6 mmoles), 37% KF/A1203 (1.4755 g, 3 w/w) and 18-crown-6 (0.1255 g, 0.36 mmoles) in sieve-dried 25 acetonitrile (5 mL) was refluxed at 90'C under a N2 atmosphere for 1 hr. The reaction was allowed to cool to ambient temperature. The WO 99/20270 PCT/US98/22111 -71 insoluble solids present in the reaction were filtered off and washed with EtOAc. The filtrate was collected and concentrated in vacuo to give a black/red solid (1.1487 The product was purified by plate layer chromatography with a mixture of 2:1 hexane/CH2Cl2 to afford the desired product as a yellow solid (0.7095 g).

1 H NMR (CDC13) 5: 3.82 3H), 6.90 (dd, 1H), 7.01 (dd, 1H), 7.12- 7.23 3H), 7.33-7.39 2H), 8.22 (dd, 1H).

Step B: To a stirred solution of the product obtained from Step A (0.7095 g, 2.7 mmoles) in absolute EtOH (7 mL) was added SnCl2*H20 (1.8563 g, 8.1 mmoles). The resulting mixture was refluxed at 90 0 C for 1.5 hrs under an atmosphere of N2. The reaction was cooled to ambient temperature, poured into a mixture of ice, brine, and 5 N NaOH, and extracted with EtOAc The organic layers were combined, washed with brine, and dried over Na2SO4. Concentration in vacuo afforded the desired product as a yellow oil (0.6826 The product was purified by plate layer chromatography with 1:1 CH2C12/hexane to give the desired amine.

1 H NMR (CDC13) 5: 3.72 3H), 4.29 (br s, 2 6.62-6.69 3H), 6.73-6.80 2H), 7.11 1H), 7.21 1H), 7.44 (dd, 1H).

Step C: To a thick slurry of the amine (0.277 g, 1.74 mmoles) from Step B in 2 N HCI (1.76 mL) and HOAc (0.54 mL) was added absolute EtOH (1.76 mL) to solubilize the mixture. The stirred mixture was cooled to 0 C and a solution of NaNO2 (0.1552 g, 2.09 mmoles) in water (0.2 mL) was added under N2. The resulting light brown solution was stirred at 0°C for 20 min. before adding a 93.1 mg/mL aqueous solution of KPF6 (2.7 mL). Upon addition, yellow solid immediately precipitated out of solution. The yellow/brown solid was collected by vacuum filtration WO 99/20270 PCT/US98/22111 -72 and washed with cold water (2X) and cold Et20 After drying in vacuo over 18 hrs, the diazonium salt was collected as a yellow solid (0.3149 g).

1 H NMR (d6-acetone) 5: 3.83 3H), 7.16 (dd, 1H), 7.27 1H), 7.27- 7.30 (dd, 1H), 7.47 1H), 7.79 1H), 7.88 1H), 8.18 1H), 8.84 (dd, 1H).

Step D: A solution of FeSO4-7H20 (0.2258 g, 0.81 mmoles) in distilled water (3 mL) was heated to 100 0 C. The diazonium salt from Step C was added in one portion and the resulting mixture was stirred at 100 0

C

under N2. Gas evolution was observed for the first 5-10 min. of the reaction. With time, the product oiled out of solution. After 30 min., the reaction was partitioned between EtOAc and ice/brine. The organic layer was collected, dried over Na2SO4, and concentrated in vacuo to give a green/brown oil (0.3317 The crude material was purified by plate layer chromatography with 20% CH2C12/hexane to afford the desired product as a white solid (0.040 g).

1 H NMR (CDC13) 5: 4.07 3H), 6.89 1H), 7.36-7.45 4H), 7.80 (dd, 1H), 8.64 (dd, 1H).

Step E: To a stirred solution of the dibenzothiophene (0.040 g, 0.19 mmoles) isolated from Step D in HOAc (2.5 mL) was added 40% HBr (0.65 mL, 5.6 mmoles) under N2. The reaction was heated to 130 0 C for 20 hrs.

The resulting green solution was partitioned between EtOAc and ice/brine. The organic layer was washed with sat. NaHCO3 (2X) and brine. The EtOAc extract was dried over Na2SO4 and concentrated in vacuo to give an off-white solid (0.0366 Purification by plate layer chromatography with 1:1 hexane/CH2Cl2 afforded the desired phenol as a white solid (0.0294 g).

WO 99/20270 PCT/US98/22111 -73 1 H NMR (CDC13) 8: 5.53 1H), 6.77 1H), 7.26 1H), 7.43-7.49 3H), 7.82 (dd, 1H), 8.63 (dd, 1H).

PREPARATIVE EXAMPLE 7: PREPARATION OF T-BUTYLDIMETHYLSILYLOXYMETHYL

DIBENZOTHIOPHENE

OH

S

OTBS

Step A: 2-Bromo-3-nitrotoluene and 3-methoxy benzenethiol were coupled using the procedures described in Example 6 (Step A) to afford the desired product as a yellow oil.

1 H NMR (CDC13) 5: 2.38 3H), 3.73 3H), 6.62-6.66 2H), 6.68 (dd, 1H), 7.11 1H), 7.39 2H), 7.53 (dd, 1H).

Step B: The coupled product from Step A was reduced to its corresponding amine using the procedures described in Example 6 (Step The amine was obtained as a green/yellow oil.

1 H NMR (CDC13) 5: 2.39 3H), 3.71 3H), 6.58-6.65 3H), 6.71-6.76 2H), 7.09 2H).

Step C: Utilizing the procedure described in Example 6 (Step the amine from Step B was converted to its diazonium salt. The product was isolated as a green/yellow solid.

WO 99/20270 PCT/US98/22111 -74 1 H NMR (d6-acetone) 5: 2.49 3H), 3.78 3H), 6.97-7.02 3H), 7.35 1H), 8.04 1H), 8.31 1H), 8.87 1H).

Step D: To a solution of the diazonium salt (0.9275 g, 2.3 mmoles) obtained from Step C in anhydrous DMSO (20 mL) was added 3A molecular sieves. The mixture was heated to 60°C and stirred for 1 hr. The orange mixture was filtered and the molecular sieves washed well with EtOAc. The filtrate was collected and washed with H20 (4X) followed by brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to give a dark red/orange oil. The crude material was purified by plate layer chromatography with 2:1 hexane/CH2C12 to give the desired dibenzothiophene as a white solid (0.1047 g).

1 H NMR (CDC13) 8: 2.58 3H), 4.08 3H), 6.91 1H), 7.25 (d, 1H), 7.36 2H), 7.47 1H), 8.50 1H).

Step E: Utilizing the procedure described in Example 6 (Step the product from Step D was demethylated to give the phenol as a white solid.

1H NMR (CDC13) 5: 2.58 3H), 6.77 1H), 7.24-7.31 (2d, 2H), 7.38 1H), 7.43 1H), 8.48 1H).

Step F: To a solution of the phenol (0.076 g, 0.35 mmoles) from Step E in CH2C12 (1 mL) was added NEt3 (0.059 mL, 0.42 mmoles) at 0°C under N2. The reaction was stirred for 10 min. before adding acetyl chloride (0.027 mL, 0.39 mmoles). The reaction was then stirred at 0°C for another 15 min. and poured into ice/H20. The mixture was extracted WO 99/20270 PCT/US98/22111 with EtOAc. The organic layers were washed with 1 N HCI followed by brine, and dried over Na2SO4. Concentration in vacuo gave the desired product as a light brown oil (0.1163 g).

1 H NMR (CDC13) 8: 2.53 3H), 2.57 3H), 7.19 1H), 7.27 (d, 1H), 7.38 1H), 7.43 1H), 7.73 1H), 8.08 1H).

Step G: The acetylated product (0.0902, 0.35 mmoles) obtained from Step F was dissolved in CC14 (0.5 mL) and placed under a N2 atmosphere. NBS (0.0817 g, 0.46 mmoles) was added followed by a crystal of AIBN. The reaction was heated to 80 0 C for 23 hrs. The reaction was poured into ice/brine and extracted with EtOAc. The organic layers were washed with 5% Na2S203 and brine. Concentration in vacuo gave the crude product as a yellow oil (0.2085 The oil was purified by plate layer chromatography with 1:1 hexane/CH2C12 to afford the alkyl bromide as a yellow solid (0.0895 g).

1 H NMR (CDC13) 5: 2.53 3H), 4.77 2H), 7.23 1H), 7.46-7.52 3H), 7.76 1H), 8.22 (dd, 1H).

Step H: The alkyl bromide (0.0895 g, 0.27 mmoles) from Step G was combined with KOAc (0.0541 g, 0.53 mmoles) in sieve-dried DMF (1 mL) and heated to 100 0 C for 1 hr. The reaction was poured into ice/H20 and extracted with EtOAc. The organic layers were washed with additional (2X) and brine, and dried over Na2SO4. Concentration in vacuo gave an orange/red oil (0.114 The oil was purified by plate layer chromatography with 3:1 CH2C12/hexane to give a pale yellow solid (0.0635 g).

WO 99/20270 PCT/US98/22111 -76 1H NMR (CDC13) 8: 2.17 3H), 2.55 3H), 5.38 2H), 7.21 (d, 1H), 7.44-7.49 3H), 7.73 1H), 8.22 (dd, 1H).

Step I: A yellow mixture of the product (0.0635 g, 0.2 mmoles) from Step H, N NaOH (0.1 mL, 0.42 mmoles), and absolute EtOH (1 mL) was heated to 70 0 C under N2 for 15 min. The reaction was partitioned between EtOAc and ice/1 N HC1. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo to give an orange solid (0.0637 The solid was purified by plate layer chromatography with EtOAc/CH2Cl2 to give the desired product as a slightly orange solid (0.0335g).

1 H NMR (CDC13+CD30D) 8: 4.76 2H), 6.71 1H), 7.07 1H), 7.17 1H), 7.24-7.28 2H), 8.45 1H).

Step J: To a flask charged with the phenol (0.0335 g, 0.16 mmoles) from Step I was added a solution of TBSCI (0.0305 g, 0.17 mmoles) in DMF mL) under N2. The reaction was cooled to 0°C and stirred for 10 min.

before adding dropwise a solution of imidazole (0.0137g, 0.19 mmoles) in DMF (0.25 mL). The solution was stirred at 0°C for 1 h. The reaction was partitioned between EtOAc and ice/i N HC1. The organic layer was washed with brine, dried over Na2S04, and concentrated in vacuo to give a light brown oil. The oil was purified by plate layer chromatography with 3:1 CH2Cl2/hexane to afford the TBS-protected alcohol as a light yellow solid (0.0416 g).

1 H NMR (CDC13) 5: 0.15 3H), 0.98 6H), 4.97 2H), 6.76 (d, 1H), 7.26 1H), 7.45-7.48 3H), 8.55 (dd, 1H).

WO 99/20270 PCT/US98/22111 -77 PREPARATIVE EXAMPLE 8: PREPARATION OF T-BUTYLDIMETHYLSILYLOXYPROPYL

DIBENZOTHIOPHENE

OH

TBSO

Step A: The acetylated dibenzothiophene (0.3985, 1.55 mmoles) obtained from Example 7 (Step F) was dissolved in CC14 (5 mL) and place under a N2 atmosphere. Recrystallized NBS (0.3051 g, 1.7 mmoles) was added followed by a crystal of AIBN. The reaction was heated to 80°C for 23 hrs. Additional NBS (0.3067 g, 1.7 mmoles) was added to the reaction and the mixture was stirred at 80 0 C for another 6.5 hrs. The reaction was poured into ice/brine and extracted with EtOAc. The organic layers were washed with 5% Na2S203 and brine. Concentration in vacuo gave an orange solid (0.5974 By 1 H NMR analysis, the crude product contained a 3:1 mixture of the desired dibrominated product to the monobrominated product or the dibrominated product.

1 H NMR (CDC13) 8: 2.55 3H), 6.96 1H), 7.25 1H), 7.48-7.50 2H), 7.76 2H), 8.24 1H).

Step B: The crude alkyl bromide (0.4670 g, 1.1 mmoles) from Step A was dissolved in sieve-dried DMF (5 mL) and placed under N2. KOAc (0.3396 g, 3.4 mmoles) was added in one portion and the reaction was heated to 100 0 C. After 1.5 hrs, The reaction was partitioned between EtOAc and H20. The organic layer was washed with water (3X) and brine, dried over Na2SO4, and concentrated in vacuo to give a WO 99/20270 PCT/US98/22111 78 brown/yellow oil (0.6382 The oil was purified by plate layer chromatography with 4 elutions using 3:2 CH2Cl2/hexane to give 2 major fractions: 1) the triacetate compound (0.1403 g) and 2) a mixture of the diacetate compound and the aldehyde (0.2077 g).

1 H NMR (CDC13) 6: 2.18 6H), 2.55 3H), 7.23 1H), 7.47 (t, 2H), 7.61 1H), 7.75 1H), 7.93 1H), 8.31 (dd, 1H).

Step C: The fraction from Step B containing the triacetate compound (0.1255 g, 0.4 mmoles) was suspended in absolute EtOH (2 mL) and 5 N NaOH (0.15 mL, 0.8 mmoles) was added under N2. The reaction was heated to 70 0 C for 20 min. then poured into ice/l M HC1. The mixture was extracted with EtOAc. The organic layer was collected, washed with brine, dried over Na2SO4, and cocentrated in vacuo to give an orange solid (0.1065 The solid was purified by plate layer chromatography with 5% EtOAc/CH2C12 to afford the clean aldehyde as a yellow solid (0.0756 g).

1 H NMR (CDC13+d6-acetone) 6: 6.73 1H), 7.07 1H), 7.21 (d, 1H), 7.40 1H), 7.73 1H), 8.78 (dd, 1H), 9.00 (bs, 1 10.04 (s, 1H).

Step D: The fraction from Step B containing a mixture of the diacetate compound and the aldehyde (0.2077 g, 0.77 moles) was submitted under the same reaction conditions described in Step C. The resulting mixture of aldehyde and diol was separated by plate layer chromatography with EtOAc/CH2Cl2 to give 0.0895 g of clean aldehyde.

WO 99/20270 PCT/US98/22111 -79 Step E: The aldehydes from Step C and Step D were combined and acetylated using the procedures described in Example 7 (Step The reaction was stirred at 0°C for a total of 30 min. The desired product was isolated as tan solid.

1 H NMR (CDC13) 8: 2.57 3 7.29 1H), 7.50 1H), 7.65 (t 1H), 7.82 1H), 7.99 (dd, 1H), 8.54 (dd, 1H), 10.29 1H).

Step F: The acetylated product (0.1572 g, 0.58 mmoles) from Step E was dissolved in CH2C12 (3 mL) and methyl (triphenylphosphoranylidene)acetate (0.2141 g, 0.64 mmoles) was added under N2. The mixture was stirred at ambient temperature for 1.5 hrs. The reaction was concentrated in vacuo to give a white/yellow solid. The solid was purified by plate layer chromatography with 5% hexane/CH2Cl2 to give the desired ester as a white solid (0.1688g).

1 H NMR (CDC13) 5: 2.54 3 3.86 3H), 6.67 1H), 7.24 (d, 1H), 7.48 (t 2H), 7.66 1H), 7.77 1H), 7.95 1H), 8.28 1H).

Step G: To a solution of the ester obtained from Step F (0.1688 g, 0.51 mmoles) in 1:1 EtOAc/EtOH was added 10% Pd/C (0.0186, 10% The resulting mixture was degassed with N2 and hydrogenated under atmospheric H2 pressure for 3 hrs. The reaction was degassed with N2 and the catalyst removed by filtering through a celite pad. The filtrate was concentrated in vacuo to give a white/yellow solid (0.1595 g).

WO 99/20270 PCT/US98/22111 1 H NMR (CDC13) 5: 2.53 3 2.80 2H), 3.21 2H), 3.70 (s, 3H), 7.21 1H), 7.31 1H), 7.40-7.49 2H), 7.73 (dd, 1H), 8.12 (dd, 1H).

Step H: The alkyl ester isolated from Step G (0.1595 g, 0.49 mmoles) was dissolved in absolute EtOH (2 mL), and 5 N NaOH (0.29 mL, mmoles) was added under N2. The resulting yellow mixture was heated to 70 0 C. After 1 hr, the reaction was partitioned between ice/i M HCI and EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo to afford the desired acid as a pale yellow solid (0.1614 g).

1H NMR (CDC13+d6-acetone) 6: 2.77 2H), 3.15 2H), 6.81 (d, 1H), 7.18-7.26 2H), 7.32 1H), 7.32 1H), 8.52 1H).

Step I: To a solution of the carboxylic acid generated in Step H (0.1614, 0.49 mmoles) in distilled THF (5 mL) was added dropwise a 1 M solution of BH3-THF in THF (0.98 mL, 0.98 mmoles). Upon addition, gas evolution was observed. With time, the reaction became a cloudy green mixture. The reaction was stirred at ambient temperature for a total of 2 hrs. The reaction was quenched with dropwise addition of MeOH until no further gas evolution was observed. The reaction mixture was concentrated in vacuo and the residue was purified by plate layer chromatography with 5% EtOAc/CH2Cl2 to give the desired diol as a white solid (0.1065 g).

1 H NMR (CDCl3+d6-acetone) 8: 1.88 2H), 2.81 2H), 3.57 (t, 2H), 6.74 1H), 7.08 2H), 7.10 1H), 7.21-7.27 2H), 8.42 1H), 8.69 (bs, 1 H).

WO 99/20270 PCT/US98/22111 -81 Step J: Utilizing the procedure described in Example 7 (Step the diol obtained from Step I was selectively protected at the primary alcohol position to give the desired TBS-protected product as a yellow oil after plate layer chromatography with 5% EtOAc/CH2C12.

1 H NMR (CDC13) 5: 0.07 3H), 0.92 6 1.99 2H), 2.92 (t, 2H), 3.70 2H), 6.74 1H), 7.24-7.27 2H), 7.38-7.43 2H), 8.48 1H).

PREPARATIVE EXAMPLE 9: PREPARATION OF T-BUTYLDIMETHYLSILYLOXYMETHYL

DIBENZOFURAN

OH

0

TBSO

Step A: To a mixture of 2,6-difluoronitrobenzene (1.0 g, 6.3 mmoles) in MeOH mL) was added a 4.4 M solution of NaOMe in MeOH (1.57 mL, 6.9 mmoles). The mixture was heated to 70 0 C for 20 min. The resulting orange reaction mixture was concentrated in vacuo. The residue was dissolved in EtOAc and washed with H20 and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to give a pale yellow solid. The solid was purified by plate layer chromatography with 1:1 Shexane/CH2Cl2 to give clean product as a pale yellow solid (1.0559 g).

1 H NMR (CDC13) 5: 3.89 3H), 6.77-6.85 2H), 7.36-7.41 (m, 1H).

WO 99/20270 PCT/US98/22111 82 Step B: The methoxy nitrobenzene isolated from Step A was coupled with ocresol (0.64 mL, 6.2 mmoles) using the procedures described in Example 6 (Step A) with the exception that the reaction time was 3 hrs.

After purification by plate layer chromatography with 1:1 hexane/CH2Cl2, the desired adduct was obtained as a pale yellow solid.

1 H NMR (CDC13) 8: 2.18 3H), 3.91 3H), 6.27 1H), 6.66 (d, 1H), 6.98 1H), 7.10-7.27 4H).

Step C: The adduct from Step B (1.3924 g, 5.4 mmoles) was hydrogenated under 40-46 psi of H2 in a Parr Shaker for 5 days using 10% Pd/C (0.139 g, 10 w/w) in 1:1 EtOH/EtOAc. The catalyst was filtered off through a celite pad and the filtrate was concentrated in vacuo. The product was obtained as a yellow oil (1.2833 g).

1 H NMR (CDC13) 5: 2.30 3H), 3.88 3H), 6.36 1H), 6.60 (m, 2H), 6.79 1H), 6.97 1H), 7.08 1H), 7.21 1H).

Step D: The amine from Step C was converted to its KPF6 diazonium salt using the procedures described in Example 6 (Step The product was isolated as a yellow solid.

1 H NMR (d6-acetone) 8: 2.26 3H), 4.36 3H), 6.57 1H), 7.25 1H), 7.32 1H), 7.38 2H), 7.46 (dd, 1H), 8.17 1H).

WO 99/20270 PCT/US98/22111 -83 Step E: A mixture of 0.438 g (0.48 mmoles) of Pd2(dba)3 in anhydrous DMSO mL) was heated to 100 0 C under N2 and the diazonium salt from Step D (1.8489 g, 4.8 mmoles) was added in one portion, resulting in significant gas evolution. The reaction was stirred at 100 0 C for 40 min and then filtered through celite. The filtrate was paritioned between EtOAc and water. The organic layer was washed well with H20 (2X) followed by brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to give a black solid. The solid was purified by plate layer chromatography with 2:1 hexane/CH2Cl2 to give the desired product as a white solid (0.4335 g).

1 H NMR (CDC13) 5: 2.59 3H), 4.05 3H), 6.77 1H), 7.20-7.27 3H), 7.35 1H), 7.95 (dd, 1H).

Step F: The dibenzofuran from Step E was demethylated and acetylated using the procedures described in Example 6 (Step E) and Example 7 (Step F) respectively. The desired product was obtained as a white solid over the 2 steps.

1 H NMR (CDC13) 8: 2.50 3H), 2.58 3H), 7.11 (dd, 1H), 7.21- 7.30 2H), 7.41-7.50 2H), 7.64 (dd, 1H).

Step G: 0.1126 g (0.49 mmoles) of acetylated dibenzofuran from Step F, recrystallized NBS (0.0970 g, 0.54 mmoles), benzoyl peroxide (0.0271 g, 0.099 mmoles), and CCl4 (3 mL) were combined under N2 and heated to 100 0 C. In addition to heating, the reaction was illuminated with a sun lamp. Within 30 min., the reaction became dark purple.

After 2 hrs, another 0.3 equivalents of NBS and 0.0312 g of benzoyl WO 99/20270 PCT/US98/22111 -84 peroxide were added. The reaction was heated for another 2 hrs, and then partitioned between EtOAc and 5% Na2S203. The organic layer was washed with H20 and brine, dried over Na2SO4, and concentrated in vacuo to give a dark purple solid. The solid was purified by plate layer chromatography with 2:1 CH2Cl2/hexane to afford the desired alkyl bromide as an off-white solid (0.081 g).

1 H NMR (CDC13) 5: 2.50 3H), 4.84 2H), 7.16 (dd, 1H), 7.30 (t, 1H), 7.47-7.55 3H), 7.77 (dd, 1H).

Step H: The diacetate was prepared after plate layer chromatography with 2:1 CH2C12/hexane, from the alkyl bromide of Step G using the procedures described in Example 7 (Step H).

1 H NMR (CDC13) 5: 2.14 3H), 2.51 3H), 5.49 2H), 7.15 (dd, 1H), 7.32 1H), 7.44-7.52 3H), 7.80 (dd, 1H).

Step I: The diacetate from Step H was treated under the same conditions as Example 7 (Step I) to give the crude diol.

1 H NMR (CDC13+CD30D) 5: 5.00 2H), 6.67 1H), 7.03 1H), 7.19-7.30 2H), 7.38 (dd, 1H), 8.02 (dd, 1H).

Step J: The diol from Step I was selectively protected at the primary position using the procedures described in Example 7 (Step J) to give the desired product as a white solid after plate layer chromatography with 2:1 CH2C12/hexane.

WO 99/20270 PCT/US98/22111 1 H NMR (CDC13) 8: 0.15 3H), 0.97 6H), 5.15 2H), 6.68 (d, 1H), 7.15 1H), 7.25 1H), 7.33 1H), 7.53 1H), 7.98 1H).

PREPARATIVE EXAMPLE 10: PREPARATION OF 3-

HYDROXYBIPHENYL

A stirred mixture of 660mg(3mmol) of 3-iodophenol, 439mg (3.6mmol) phenylboronic acid, and 173mg (0.15mmol) tetrakistriphenylphosphine in 10mL of toluene, 5mL ethanol, and 6mL 2M sodium carbonate (aqueous) was heated at 100oC in an inert atmosphere of nitrogen for 15 minutes. The cooled mixture was partitioned between EtOAc, ice, and brine and the organic phase was separated, washed with brine, dried over anhydrous Na2SO4, filtered and evaporated. The residue was purified by plate layer chromatography (PLC) using CH2C12 as the eluant to give 430mg of the titled product.

1 H NMR (CDC13) 5: 1.26 J=7.3Hz,3H), 1.47 J=6.3Hz, 3H), 3.47 (dd, J=3.0, 11Hz, 1H-6), 3.50 1H-1), and 4.2 (dd, J=3.0, 10Hz, 1H- PREPARATIVE EXAMPLE 11: PREPARATION OF 4'-T- BUTYLDIPHENYLSILYLOXYMETHYL-3-HYDROXYBIPHENYL As described in Example 10, 391mg (1 mmol) of 4-tbutyldiphenylsilyloxymethylboronic acid (prepared as exemplified in US 5,192,758) and 220 mg (1 mmol) of 3-iodophenol gave 354.3mg of the title compound.

WO 99/20270 PCT/US98/22111 -86 PREPARATIVE EXAMPLE 12: PREPARATION OF 4-HYDROXY-

FLUORENE

A partial solution of 196.2mg (1 mmol) of 4-hydroxy-fluoren-9-one in 2mL EtOAc and 3 mL EtOH with 40mg 10% Pd/C was stirred under a balloon of hydrogen for 27.5 hours. The catalyst was removed by filtration through celite, washed well with EtOAc, and the filtrate evaporated. The residue was purified by plate layer chromatography with CH2Cl2-EtOAc(50:1) to give 102.7mg of the title substance.

1 H NMR (d6-acetone) 6: 3.88 CH2).

PREPARATIVE EXAMPLE 13: PREPARATION OF 4-HYDROXY-9-

CARBOMETHOXY-FLUORYLIDENE

A stirred mixture of 401mg (2 mmol) of 4-hydroxy-fluoren-9-one and 1.37g (4.1mmol) of methyl-(triphenylphosphoranylidene)-acetate in of toluene was refluxed under an atmosphere of nitrogen for 65.5 hours. The cooled reaction mixture was evaporated and the residue purified by plate layer chromatography using CH2Cl2-EtOAc (50:1) as eluant to give 433mg of the title compound as a mixture of isomers.

1 H NMR (CDC13) 8: 3.87 3H), 3.88 3H), 6.74-8.89 8H).

PREPARATIVE EXAMPLE 14: PREPARATION OF 4-HYDROXY-9-

CARBOMETHOXYMETHYL-FLUORENE

A stirred mixture of 348mg (1.38 mmol) of the fluorylidene derivative prepared in Example 28, Step A, and 50mg of 10% Pd/C in lOmL of EtOAc-EtOH was hydrogenated under balloon pressure at ambient temperature for 2.5 hours. The catalyst was removed by filtration through celite, washed well with EtOAc, and the filtrate evaporated and dried in vacuo to give 348.5mg of the title product.

WO 99/20270 PCT/US98/22111 -87 1 H NMR (CDC13) 8: 2.77 J=7.3Hz, 2H), 3.79 3H), 4.42 (t, J=7.3Hz,H), 5.6 OH), 6.72-8.09 7ArH).

PREPARATIVE EXAMPLE 15: PREPARATION OF 4-HYDROXY-9-

SILYOXYETHYL-FLUORENE

Step A: Preparation of 4 -Hydroxy-9-hydroxyethyl-fluorene To a stirred solution of 277.5mg (1.09mmol) of the ester prepared in Example 14 in 5mL of anhydrous THF at OOC was added dropwise 1.lmL (1.lmmol) of a 1M solution of lithium aluminum hydride in ether. The resulting mixture was stirred at 0OC under nitrogen for hours and then carefully quenched with Glaubers salt. The mixture was partitioned between EtOAc, ice, 2N HC1, and brine and the organic phase was separated, washed with brine, dried over Na2SO4, filtered, and evaporated. The residue was purified by PLC with CH2Cl2-EtOAc (10:1) to give 236.8mg of the title compound.

1 H NMR (CDC13) 8: 2.33 J= 6.8Hz, 2H), 3.57 J= 6.8Hz, 2H), 4.13 J=6.8Hz), 6.08 OH), 6.68-8.13 7ArH).

Step B: A mixture of 236.8mg (1.05mmol) of carbinol, prepared in the previous step, 173.5mg (1.15mmol) of t-butyldimethylchlorosilane, and 85.5mg (1.26mmol) of imidazole in 5mL of sieve-dried DMF was stirred at 0OC under nitrogen for 40 minutes. The mixture was partitioned between EtOAc, ice, 2N HC1, and the organic phase was separated, washed twice with ice-water and then with brine, dried over Na2SO4, filtered, and evaporated. The residue was purified by PLC with CH2C12-EtOAc (50:1) to give 325. mg of the title compound.

WO 99/20270 PCT/US98/22111 -88 1 H NMR (CDC13) 8: 0.03 6H), 0.88 9H), 2.19(m, 2H), 3.67 (t, J= 6.8Hz, 2H), 4.13 J=6.4Hz), 5.12 OH), 6.71-8.10 7ArH).

PREPARATIVE EXAMPLE 16: PREPARATION OF 4-HYDROXY-9-

E.Z-T-BUTYLDIMETHYLSILYLOXYETHENYL-FLUORENE

StepA: Preparation of 4 -Acetoxy-9-(2-t-butyldimethylsilyloxyethyl)fluorene To a stirred solution of a mixture of 1.91g (5.6 mmol) of the phenol, prepared in Step B of Example 15, and 736.6mg (7.28 mmol) of triethylamine in 20mL of CH2C12 at OOC was added 527.5mg (6.72 mmol) of neat acetyl chloride and the mixture was stirred further for 0.5 hour. The mixture was partitioned between EtOAc, ice, IN HC1, and brine and the organic phase was separated, washed with brine, dried over Na2SO4, filtered, evaporated, and dried in vacuo to give 2.14g of crude product which was used without further purification.

1 H NMR (CDC13) 5: 0.86 9H), 2.47 3H).

StepB: Preparation of 4-Acetoxy-9-bromo-9-(2-tbutyldimethylsilyloxyethyl)-fluorene A mixture of 2.14g (5.6 mmol) of material prepared in the previous step, 1.2g (6.72 mmol) of N-bromosuccinimide, and a pinch of AIBN in of carbon tetrachloride was refluxed under nitrogen for hours. The cooled mixture was partitioned between EtOAc, ice, aqueous sodium thiosulfate, and brine and the organic phase was separated, washed with brine, dried over Na2SO4, filtered, evaporated, and dried in vacuo to give the crude, title product which was used without further purification.

WO 99/20270 PCT/US98/22111 -89 1 H NMR (CDC13) 5: 0.73 9H), 2.47 3H), 2.91 2H), 3.20 (m, 2H).

Step C: Preparation of 4-Acetoxy-9-E,Z-t-butyldimethylsilyloxyethenylfluorene A mixture of the crude product from the previous step, 913mg (10.9 mmol) of NaHCO3, and 1.54g (5.98 mmol) of silver triflate in DMSO was stirred at room temperature for 15 minutes. The mixture was diluted with EtOAc, filtered through celite to remove the insoluble materials, and washed thoroughly with EtOAc. The filtrate was partitioned between EtOAc, ice, and brine and the organic phase was separated, washed twice with ice-water, and then with brine, dried over Na2SO4, filtered, evaporated, and dried in vacuo. Purification by PLC eluted with CH2Cl2-hexanes gave 1.22g of product, as a mixture of geometric isomers.

1 H NMR (CDC13) 6: 0.17 6H), 0.98 9H), 2.48 3H), 5.02 (m, 2H).

Step D: To a stirred, warm solution of 1.19g (3.13 mmol) of acetate, prepared in the previous step, in 20mL EtOH was added dropwise 0.77mL (3.85 mmol) of a 5N solution of sodium hydroxide in water. The resulting dark solution was stirred further for 5 minutes and then partitioned between EtOAc, ice, 1N HC1, and brine. The organic phase was separated, washed with brine, dried over Na2SO4, filtered, evaporated, and dried in vacuo. Purification by PLC eluted with CH2C12 gave 890.0mg of product, as a mixture of geometric isomers.

1 H NMR (CDC13) 5: 0.15 6H), 0.96 9H), 4.98 2H), 5.18 5.22 (2s's, 1-OH), 6.68-8.1 8H).

WO 99/20270 PCT/US98/22111 PREPARATIVE EXAMPLE 17:PREPARATION OF 4-HYDROXY-7- T-BUTYLDIMETHYLSILYLOXYMETHYL-FLUOREN-9-ONE Step A: Preparation of 2-Methoxy-6-carbomethoxy-4'-t-butyldiphenylsilyloxymethylbiphenyl Using the procedure described Example 10, 10.0g (34.2mmol) of methyl- 2 -iodo-3-methoxybenzoate (prepared as outlined by W. M.

Stanley, E. McMahon, and R. Adams, J. Amer. Chem. Soc. 1933, 706) was refluxed for 5 hours to give after chromatography on silica gel with CH2Cl2-hexanes 12. g of the title compound.

1 H NMR (CDC13) 5: 1.14 9H), 3.57 3H), 3.78 3H), 7.1-7.77 ArH).

Step B: Preparation of 2-Methoxy-4'-hydroxymethylbiphenyl-6carboxylic acid A stirred mixture of 6.0g (11.7mmol) of biphenyl derivative prepared in Step A and 4.7mL of 5N NaOH in 100mL of EtOH was refluxed in an inert atmosphere of nitrogen for 4 hours. The mixture was partitioned between EtOAc, ice, 2N HC1, and the organic phase was separated, washed with brine, dried over Na2SO4, filtered, evaporated, and dried in vacuo. Upon addition of a little CH2C12 the product crystallized and after the addition of some hexanes 1.95g of the product was collected by filtration and dried in vacuo.

1 H NMR (d6-acetone) 5: 3.74 3H), 4.64 2H), 7.17-7.44 (m, 7ArH).

Step C: Preparation of 4 -Methoxy-7-chloromethyl-fluoren-9-one WO 99/20270 PCT/US98/22111 -91 To a stirred suspension of 2.0g (7.74mmol) of acid prepared in Step B in 40mL of sieve- dried CH2C12 at OOC was added all at once 3.55g (17.0mmol) of phosphorous pentachloride and the mixture was stirred further for 5 minutes, and then for 1 hour with the ice-water bath removed. The homogenous solution was recooled to 0OC, and 1.55g (11.6mmol) of A1C13 was added all at once. The resulting mixture was stirred further for 0.5 hour and then partitioned between EtOAc, ice, and brine. The organic phase was separated, washed with brine and saturated NaHCO3, dried over Na2SO4, filtered, evaporated, and dried in vacuo to give 2.04g of the title material as a yellow solid, which was used without further purification.

IR (CH2C12): 1717.5cm-1; 1 H NMR (CDC13) 8: 3.90 3H), 4.53 2H), 6.94-7.68 6ArH).

Step D: Preparation of 4-Methoxy-7-acetoxymethyl-fluoren-9-one A mixture of 2.0g (7.7mmol) of material prepared in Step C and 1.52g (15.5mmol) of potassium acetate in 30mL of DMF was stirred at 100oC under nitrogen for 36 minutes. The cooled mixture was partitioned between EtOAc and ice-water and the organic phase was separated, washed twice with ice-water, and then with brine, dried over Na2SO4, filtered, evaporated, and dried in vacuo to give 2.17g of the title material as a yellow solid, which was used without further purification.

IR (CH2C12): 1742, 1718cm-1; 1 H NMR (CDC13) 8: 2.12 3H), 3.99 3H), 5.10 2H), 7.04-7.81 6ArH).

Step E: Preparation of 4 -Methoxy-7-hydroxymethyl-fluoren-9-one A stirred mixture of the acetate prepared above and 3.07mL (15.4mmol) of 5N NaOH in 100mL of EtOH was refluxed under nitrogen for 10 minutes. The cooled mixture was partitioned between WO 99/20270 PCT/US98/22111 -92 EtOAc, ice-water and 2N HC1, and the organic phase was separated, washed with brine, dried over Na2SO4, filtered, evaporated, and dried in vacuo to give 2.07g of the title material as a yellow solid, which was used without further purification.

1 H NMR (CDC13) 8: 3.96 3H), 4.68 2H), 7.01-7.77 6ArH).

Step F: Preparation of 4-Methoxy-7-formyl-fluoren-9-one To a stirred suspension of 1.85g (7.69mmol) of carbinol from Step E in CH2C12 was added 270. 1mg (0.769mmol) of tetrapropylammonium perruthenate. After stirring for 5 minutes, 1.35g (11.5mmol) of solid N-methyl-morpholine-N-oxide was added all at once, and the resulting mixture stirred further for 5 minutes. The dark solution was passed over a column of florisil eluted with CH2Cl2-EtOAc (10:1) to give 1.42g of the title aldehyde as a yellow solid.

IR (CH2C12): 1720, 1698cm- 1 1 H NMR (CDC13) 5: 4.02 3H), 7.09-8.1 6ArH), 10.0 1H).

Step G: Preparation of 4-Hydroxy-7-formyl-fluoren-9-one A stirred mixture of the methylether from the previous step and of 48%HBr in 15mL of acetic acid was heated at 1300C under nitrogen for 7 hours. The cooled mixture was poured onto ice-water and the separated product collected by suction filtration, washed well with water, and dried in vacuo to give 0.94g of the title compound.

1 H NMR (d6-acetone) 8: 7.18-8.15 6ArH), 9.8 1-OH), 10.07 (s,1-CHO).

Step H: Preparation of 4-Hydroxy-7-hydroxymethyl-fluoren-9-one WO 99/20270 PCT/US98/22111 -93 A stirred mixture of 4 05.2mg (1.8mmol) of aldehyde prepared in Step G and 804.3mg (3.8mmol) of sodium triacetoxyborohydride in 27mL of anhydrous THF was refluxed under nitrogen for 1 hour. The cooled mixture was partitioned between EtOAc, ice-water and saturated NaHCO3, and the organic phase was separated, washed with brine, dried over Na2SO4, filtered, evaporated, and dried in vacuo. Purification by PLC with CH2C12-EtOAc yielded 303.7mg of the crystalline, title product.

1 H NMR (d6-acetone) 8: 4.66 7.08-7.86 6ArH), 9.38 1-

OH).

Step I: A mixture of 332.2mg (1.47mmol) of the diol from Step H, 2 43.5mg (1.61mmol) of t-butyldimethylchlorosilane, and 120mg (1.76mmol) of imidazole in 8mL of sieve dried DMF was stirred at OOC for minutes. The mixture was partitioned between EtOAc, ice-water and 2N HCI, and the organic phase was separated, washed twice with ice-water, and then with brine, dried over Na2SO4, filtered, evaporated, and dried in vacuo. Purification by PLC using CH2Cl2-EtOAc (50:1) gave 447.4mg of the title material.

1H NMR (d6-acetone) 8: 0.14 6H), 0.95 9H), 4.81 7.08- 7.86 6ArH), 9.35 (bs, 1-OH).

PREPARATIVE EXAMPLE 18: PREPARATION OF 4-HYDROXY-7- (3-T-BUTYLDIMETHYLSILYLOXYPROPYL)-FLUOREN-9-ONE Step A: Preparation of 4 -Acetoxy-7-formyl-fluoren-9-one To a stirred suspension of 1.53g (6.83mmol) of 4-hydroxy-7-formylfluoren-9-one, prepared in Step G of Example 43, in 25mL THF at 0OC was added 1.24mL 8 .88mmol) of triethylamine and 0.58mL (8.2mmol) WO 99/20270 PCT/US98/22111 -94 of acetyl chloride. The mixture was stirred further for 0.5 hour and then partitioned between EtOAc, ice, IN HC1, and brine. The organic phase was separated, washed with brine, dried over Na2SO4, filtered, evaporated, and dried in vacuo. Purification by chromatography on silica gel using methylene chloride as eluant gave 1.46g of the title compound.

IR (CH2C12): 1772, 1724, 1702, 1618,1606cm-1; 1 H NMR (CDC13) 8: 2.48 3H), 7.38-8.15 6ArH), 10.0 1H).

Step B: Preparation of 4 -Acetoxy-7-(E-2-carbomethoxyvinyl)-fluoren- 9-one A mixture of 1.46g (5.49mmol) of aldehyde, prepared in Step A, and 2.02g (6.04mmol) of methyl-(triphenylphosphoranylidene)-acetate in of methylene chloride was stirred at room temperature for 1 hour, during which time product precipitation was progressive. Etherhexanes 20mL) was added and the yellow solid was collected by suction filtration, washed with 60mL of ether-hexanes and dried in vacuo to give 1.43g of the title material.

1 H NMR (CDC13) 5: 2.48 3H), 3.82 3H), 6.49 J=16Hz, 1H), 7.30-7.87 6ArH), 7.68 J=16Hz, 1H).

Step C: Preparation of 4-Acetoxy-7-(2-carbomethoxyethyl)-fluoren-9one The material prepared above in Step B, 1.1 1g (3.45mmol) and 267mg of 5%Rh/C in 60mL methylene chloride and 12mL methanol was stirred under balloon pressure of hydrogen for 5 hours. The catalyst was removed by filtration through celite, washed well with methylene chloride, and the filtrate evaporated and dried in vacuo to give 1.lg of product which was used without further purification.

WO 99/20270 PCT/US98/22111 1 H NMR (CDC13) 5: 2.46 3H), 2.65 J=7.5Hz, 2H), 2.98 (t, 2H), 3.67 3H), 7.23-7.56 6ArH).

Step D: Preparation of 2 4 -Hydroxy-7-fluoren-9-one)propionic acid A stirred mixture of 1.27g (3.92mmol) of ester, prepared in Step C above, and 2.43mL (12.2mmol) of 5N NaOH in 30 mL of EtOH was refluxed under nitrogen for 70 minutes. The cooled mixture was partitioned between EtOAc, ice, 2N HC1, and brine, and the organic phase was separated, washed with brine, dried over Na2SO4, filtered, evaporated, and dried in vacuo to give 1.04g of the title acid.

1 H NMR (d6-acetone) 8: 2.67 J=7.5Hz, 2H), 2.97 J=7.5Hz, 2H), 7.08-7.80 6ArH), 9.37 bs, 1H).

Step E: Preparation of 4 -Hydroxy-7-(3-hydroxypropyl)-fluoren-9-ol To a stirred suspension of the acid (905.1mg,3.38mmol), prepared above in Step D, in 30mL of anhydrous THF at ambient temperature was added cautiously 10.1mL of 1M borane-THF in THF. The resulting mixture was stirred further for 2 hours and carefully quenched with methanol. The mixture was evaporated and the residue partitioned between EtOAc, ice, saturated NaHCO3, and brine, and the organic phase was separated, washed with brine, dried over Na2SO4, filtered, evaporated, and dried in vacuo to give 0.96g of the title triol.

1 H NMR (d6-acetone) 8: 1.85 2H), 2.74 J=7.4Hz, 2H), 3.60 (t, J=7.4Hz, 2H),5.49 J=6.1Hz, 1H), 6.83-7.91 6ArH), 8.88 1H).

Step F: Preparation of 4 -Hydroxy-7-(3-hydroxypropyl)-fluoren-9-one A stirred mixture of 870mg (3.38mmol) of triol, prepared in Step E, and 958mg (13.5mmol) of manganese dioxide in 20mL of acetone was refluxed for 17 hours. The cooled mixture was filtered through celite, WO 99/20270 PCT/US98/22111 -96 washed well with acetone, and the filtrate evaporated and dried in vacuo to give 832.2mg of the title compound, as a brick-red solid.

1 H NMR (d6-acetone) 5: 1.85 2H), 2.74 J=7.4Hz, 2H), 3.59 (m, 2H), 7.06-7.79 6ArH), 9.30 (s,lH).

Step G: A mixture of 832.2mg (3.28mmol) of diol, prepared in Step F above, 5 4 3.2mg (3.6mmol) of t-butyldimethylchlorosilane, and 267.7mg (3.9mmol) of imidazole in 10mL sieve-dried DMF was stirred at 0 oC for 45 minutes. The mixture was partitioned between EtOAc, ice, and 2N HC1, and the organic phase was separated, washed twice with icewater and then with brine, dried over Na2SO4, filtered, and evaporated.

The residue was purified by silica gel chromatography using an elution gradient of methylene chloride-ethyl acetate (50:1 to 10:1) to give 1.05g of the title product.

1 H NMR (CDC13) 8: 0.04 6H), 0.89 9H), 1.84 2H), 2.68 (t, J=6.3Hz, 2H), 3.62 J=6.3Hz, 2H), 5.25 (bs, 1H),5.7 J=15Hz, 1H), 6.98-7.61 6ArH) PREPARATIVE EXAMPLE 19: PREPARATION OF 4-HYDROXY-7- (3-T-BUTYLDIMETHYLSILYLOXYPROPYL)-9-

CARBOMETHOXY-FLUORYLIDENE

A stirred mixture of 110.4mg (0.3mmol) of fluorenone derivative prepared in Step G of Example 18 and 250.8mg (0.75mmol) of methyl- (triphenylphosphoranylidene)-acetate in 3mL of p-xylene was refluxed under nitrogen for 21 hours. The cooled mixture was evaporated and the residue purified by PLC with CH2C12-EtOAc (50:1) to give of the title compound as a mixture of geometric isomers.

WO 99/20270 PCT/US98/22111 97 1 H NMR (CDC13) 5: 0.07 6H), 0.92 9H), 1.87 2H), 2.73 (m, 2H), 3.65 2H), 3.87 3H), 6.71-8.74 7H).

PREPARATIVE EXAMPLE 20: PREPARATION OF 12-HYDROXY- 3.4-BENZOCOUMARIN Step A: Preparation of Methyl-2,2'-dimethoxy-biphenyl-6-carboxylate Using the procedure outlined in Example 10, 201.7mg (0.69mmol) of methyl-2-iodo-3-methoxy-benzoate and 125.9mg (0.82mmol) of 2methoxy-phenylboronic acid gave after 27 hours of reflux a quantitative yield of the title substance.

1H NMR (CDC13) 8:3.56 3H), 3.71 3H), 3.73 3H), 6.95-7.47 7H).

Step B: Preparation of 2 2 '-dimethoxy-biphenyl-6-carboxylic acid A stirred mixture of 188.4mg (0.69mmol) of ester prepared in Step A and 0.28mL (1.39mmol) of 5N NaOH in 2mL of ethanol was refluxed under nitrogen for 1.5 hours. The mixture was partitioned between EtOAc, ice, 2N HC1, and the organic phase was separated, washed with brine, dried over Na2SO4, filtered, evaporated, and dried in vacuo to give 171.6mg of the title acid which was used without further purification.

1 H NMR (d6-acetone) 5:3.66 3H), 3.71 3H), 6.79-7.48 7H).

Step C: Preparation of 1 2 -Methoxy-3,4-benzocoumarin To a stirred suspension of 171.6mg (0.67mmol) of acid prepared in Step B in 2mL of sieve-dried CH2C12 at OOC was added all at once 173.1mg (0.83mmol) of phosphorous pentachloride and the mixture was stirred WO 99/20270 PCT/US98/22111 -98 further for 5 minutes, and then for 1 hour with the ice-water bath removed. The homogeneous solution was recooled to OOC, and 133mg (0.99mmol) of A1C13 was added all at once. The resulting mixture was stirred with the ice-water bath removed for 1 hour and then partitioned between EtOAc, ice, and brine. The organic phase was separated, washed with brine, dried over Na2SO4, filtered, evaporated, and dried in vacuo. Purification by PLC with hexanes-methylene chloride (2:1) provided 134.7mg of the title compound.

1 H NMR (CDC13) 5: 3.99 3H), 7.21-8.87 7ArH).

Step D: The methylether from Step C in lmL acetic acid and 3.4mL 48%HBr was stirred at 1300C for 5 hours. The cooled solution was treated with water and the insoluble product collected by filtration, washed well with water, and dried in vacuo to give 131.3mg of the title product, which was used without further purification.

1 H NMR (d6-acetone) 5: 7.33-9.16 7H), 9.97 1H).

PREPARATIVE EXAMPLE 21 HO N NH HO F OH OTBDMS

TBDMSCI

RT.

500 mg (4.03 mmoles) of commercially available 4hydroxybenzyl alcohol was dissolved in 5.0 ml of anhydrous DMF, placed in an N2 atmosphere and chilled to 0°C. To the stirred DMF solution, 301 mg (4.33 mmoles) of imidazole was added followed by WO 99/20270 PCT/US98/22111 -99 604 mg (4.03 mmoles) of t-butyldimethylsilyl-chloride. The reaction was warmed to ambient temperature and stirred for 18 hrs.

The reaction mixture was extracted with ethyl acetate and partitioned with H20-dilute aq. sodium bicarbonate and sat. brine. The ethyl acetate extract was dried with anhydrous sodium sulfate and concentrated in vacuo to provide a viscous oil.

The crude product was purified via flash chrom. (230-400 mesh silica gel) and was eluted with a 4:1 mixture of hexanes: ethyl acetate to afford 908 mg of the silyl ether.

1H NMR (CDC13) 8: 0.10 6H), 0.94 9H), 4.66 2H), 6.08 (s, 1H), 6.72 J= 7.5 Hz, 2H), 7.14 J= 8.7 Hz, 2H).

PREPARATIVE EXAMPLE 22 HO

HO

N 12 N1 HO OTBDMS TIOAc

HOOTBDMS

CH

2 C12

R.T.

100 mg (0.418 mmoles) of the 4-hydroxy-silyl-ether was dissolved in 2.0 ml of sieve dried dichloromethane and placed in an N2 atmosphere. To the stirred dichloromethane solution, 109 mg (0.418 mmoles) of thallium acetate was added and the tan suspension was stirred for 5 min. at ambient temperature. 109 mg (0.813 mmoles) of iodine was then added. The purple suspension was stirred for 2hrs. and was filtered through a celite plug and was rinsed with 20 ml of ethyl acetate.

The ethyl acetate extract was partitioned with H20-ice and aq. sodium thiosulfate and sat. brine. The extract was dried with andydrous sodium sulfate and concentrated in vacuo to provide 108 mg of a tan solid.

The crude product was purified using plate layer chromatography with a 4:1 hexanes: ethyl acetate eluent to provide 145 mg of the iodophenol.

WO 99/20270 WO 9920270PCTIUS98/22111I -100 I H NMR (CDC13) 8: 0.07 6H), 0.90 9H), 4.60 2H), 5.18 (s, 1H), 6.91 J= 8.3 Hz, 1H), 7.15 (dd, J= 1.9 Hz, 6.3 Hz, 1H), 7.58 (d, J= 3.0 Hz, MH).

PREPARATIVE EXAMPLE 23 H 01

OH

N NH

DMF

TBDMSCI

H 0)

OTBDMS

Using the analogous procedure of example 21, the the carbinol was converted to the silyl ether in yield.

PREPARATIVE EXAMPLE 24

HO

10

OTBDMS

12 TIOAc 0H 2 C1 2

R.T.

H o) a O T B D M S Using the analogous procedure of example 22, the phenol was converted to the iodophenol.

1 H NMR (CDCI3) 5: 0.06 6H), 0.91 9H), 1.68 (in, 2H), 2.55 (t, J= 6.7 Hz, 2H), 3.58 J= 6.3 Hz, 2H), 5.22 1H), 6.88 J= 8.2 Hz, 1H), 7.05 (dd, J= 2.0 Hz, 6.3 Hz, 7.48 J= 2.0 Hz, 1H).

PREPARATIVE EXAMPLE HOJf"O

DMF

TBDMSCI

R.T.

"N OTBOMS WO 99/20270 PCT/US98/22111 101 Using the analogous procedure of example 21, the carbinol was converted to the silyl ether.

1H NMR (CDC13) 6: 0.12 6H), 0.96 9H), 5.72 2H), 6.70 (dd, J= 1.9 Hz, 4.7 Hz, 1H), 6.83-6.88 2H), 7.16 J= 7.7 Hz, 1H).

PREPARATIVE EXAMPLE 26

HO

'N

OH

12 TIOAc

CH

2

C

HOOTBDMS

OTBDMS

Using the analogous procedure of example 22, the phenol was converted to the iodophenol.

1 H NMR (CDC13) 8: 0.10 6H), 0.94 9H), 4.66 2H), 5.29 (s, 1H), 6.66 (dd, J= 1.9 Hz, 4.7 Hz, 1H), 6.97 J= 2.0 Hz, 1H), 7.56 (d, J= 7.3 Hz, 1H).

PREPARATIVE EXAMPLE 27 HO -OH

'N

NYNH

ON-

DMF

TBDMSCI

R.T.

HO OTBDMS

'N^

Using the analogous procedure of example 21, the carbinol was converted to the silyl ether.

1 H NMR (CDC13) 6: 0.08 6H), 0.88 9H), 2.76 J= 7.2 Hz, 2H), 3.78 J= 7.2 Hz, 2H), 6.65-6.69 2H), 6.76 J= 7.4 Hz, 1H), 7.12 J= 6.5 Hz, 1H).

WO 99/20270 PCT/US98/22111 -102 PREPARATIVE EXAMPLE 28 HO, ',OTBDMS 12 HO OTBDMS CH2C01 2 I

R.T.

Using the analogous procedure ofiexample 22, the phenol was converted to the iodophenol.

1 H NMR (CDC13) 8: 0.10 6H), 0.88 9H), 2.72 J= 7.0 Hz, 2H), 3.77 J= 6.9 Hz, 2H), 5.49 1H), 6.53 (dd, J= 2.0 Hz, 6.1Hz, 1H), 6.89 J= 2.0 Hz, 1H), 7.52 J= 8.0 Hz, 1H).

PREPARATIVE EXAMPLE 29 OMe OH 48% HBr HOAc COgMe 120C CO 2

H

500 mg (1.712 mmoles) of the methyl ester (Stanley, W., McMahan, Adams, R. JACS, 1933, 55, 706) was dissolved in 2.9 ml of 48% HBr and 1.49 ml of acetic acid and was placed in an N2 atmosphere. The reaction was stirred for 4 hrs. at 120 0 C. The cooled reaction mixture was basified to pH 10.0 with 2 ml of 5N aq. sodium hydroxide and partitioned with ethyl acetate-H20 and ice. The aq. layer was saved and acidified to pH 2.5 with 2.0 N aq. hydrochloric acid, forming a white solid that precipitated from solution. The solid was collected in a sintered glass funnel, washed with 10 ml of deionized and dried in vacuo to provide 286 mg of benzoic acid.

1 H NMR (d6-Me2CO) 8: 7.06 1H), 7.29 J= 8.0 Hz, 1H), 7.51 (dd, J= 1.5 Hz, 5.9 Hz, 1H).

WO 99/20270 PCT/US98/22111 -103 PREPARATIVE EXAMPLE OH OH C BH 3

.THF

THF

OH

CO

2 H R.T.

286 mg (1.08 mmoles0 of benzoic acid was dissolved in ml of anhydrous THF and was placed in an N2 atmosphere. To the stirred THF solution, 2.16 ml of borane-THF complex was added dropwise over 20 min. and the reaction was stirred for 2 hrs. at ambient temperature. 10 ml of methanol was then added to the THF solution slowly over 1 hr.

The reaction was extracted with ethyl acetate and partitioned with and sat. brine. The ethyl acetate extract was dried with anhydrous sodium sulfate and concentrated in vacuo to dryness. The crude product was purified using silica gel plate layer chromatography eluted with a 7:3 ethyl acetate: hexanes mixture to afford 120 mg of the benzyl alcohol.

PREPARATIVE EXAMPLE 31 OH OH N^ NH L. OH DMF OTBDMS

TBDMSCI

R.T.

Using the analogous procedure of example 21, the carbinol was converted to the silyl ether.

0.10 6H), 0.95 9H), 4.70 2H), 4.94 1H), 6.68 (dd, J= 2.3 Hz, 5.5 Hz, 1H), 6.83 1H), 7.16 J= 7.8 Hz, 1H).

WO 99/20270 PCT/US98/22111 -104 PREPARATIVE EXAMPLE 32: PREPARATION OF 4(R)- ACETOXY-3-(R)- 1-(T-BUTYLDIPHENYLSILYLOXY)ETHYL1- AZETIDIN-2-ONE

DPTBSO

.OAc

N

0 A mixture of 2.08g (12mmol) of 4(R)-acetoxy-3-[(R)-1-hydroxyethyl]azetin-2-one, 4.28g (15.6mmol) of t-butyldiphenylchlorosilane, and 1.22g (18mmol) of imidazole in 20mL of sieve dried DMF was stirred at ambient temperature in an inert atmosphere of nitrogen for two days.

The reaction mixture was partitioned between ether, ice-water, and 2N HC1 and the organic phase separated, washed twice with ice-water, and then brine, dried over anhydrous sodium sulfate, filtered, evaporated, and dried in vacuo. The white solid residue was recrystallized from boiling CH2Cl2-hexanes to give 3.78g of the the title product; a second crop of 0.74g of additional product was obtained from the mother liquors; total yield 4.52g.

1 H NMR (CDC13) 5: 1.03 9H), 1.12 J=6.3Hz, 3H), 3.21 (dd, J=1.3, 5.7Hz, 1H-3), 4.21 1H), 5.82 J=1.3Hz, 1H-4), 6.69 (bs, NH), 7.39-7.74 ArH).

PREPARATIVE EXAMPLE 33

DPTBSO

WO 99/20270 PCT/US98/22111 105 To a stirred solution of 2-t-butyldimethylsilyloxy-cyclohexanone (1.14g, in 10mL of sieve dried CH2C12 at OOC was added sequentially 0.56g (5.5mmol) of triethylamine and then 1.67g (7.5mmol) of trimethylsilyltriflate. The resulting mixture was stirred cold for 5minutes, and 1.03g (2.5mmol) of the azetidinone prepared in the previous example. The ice-water bath was removed and the mixture stirred further for 3 hours. The mixture was partitioned between ether, ice-water, and 2N HCI and the organic phase separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated.

The residue was purified by PLC eluting with CH2Cl2-EtOAc (50:1) to give 501.5mg of a mixture of oc-isomers, and 363.4mg of -isomers.

PREPARATIVE EXAMPLE 34 02C0

OCHO

O0 /0 To a stirred solution of 117.3 mg (0.3mmol) of trinem carbinol, prepared as described in EP 507,313, 102.3mg (0.39mmol) of triphenyl phosphine, and 15.2mg(0.33mmol) of anhydrous formic acid in 2 mL of anhydrous THF at 0OC is added 7 8.9mg(0.39mmol) of neat diisopropylazodicarboxylate. The reaction is stirred until thin layer chromatography indicated the reaction is complete and the solvent is removed by evaporation under reduced pressure. Purification by conventional silica gel chromatography provides the corresponding formate ester.

WO 99/20270 PCT/US98/22111 106 PREPARATIVE EXAMPLE A mixture of 83.8mg(0.2mmol) of formate ester prepared in the previous example and 33.6mg(0.4mmol) of sodium bicarbonate in 3mL of methanol is stirred magnetically until TLC indicates the reaction is complete. The mixture is partitioned between ethyl acetate, ice water, brine, and 2N HC1. The organic phase is separated, dried over sodium sulfate, filtered, and evaporated to give the corresponding alcohol derivative.

PREPARATIVE EXAMPLE 36 To a stirred solution of 78.2mg (0.2mmol) of the carbinol prepared in the previous example, 68.2mg (0.26mmol) of triphenylphosphine, and 70.6mg (0.22mmol) of the naphthosultam derivative prepared in example 3 in 2mL of dry THF at OOC is added 52.6mg (0.26mmol) of diisopropylazodicarboxylate. The mixture is stirred cold until TLC WO 99/20270 PCT/US98/22111 -107indicates the reaction is complete. The solvent is evaporated and the product is isolated by purification on silica gel.

PREPARATIVE EXAMPLE 37 02CO To a stirred solution of 135mg (0.195mmol) of the product of the previous example in 3mL of THF at 0OC is added 0.97mL of 0.1M aqueous triflic acid. The resulting mixture is stirred cold until TLC indicates the absence of starting material. The mixture is partitioned between ethyl acetate, ice water, brine, and saturated sodium bicarbonate solution. The organic phase is separated, dried over sodium sulfate, filtered, and evaporated. The product is purified by silica gel chromatography.

PREPARATIVE EXAMPLE 38 02CO

V

WO 99/20270 PCT/US98/22111 108 To a stirred solution of 121mg (0.195mmol) of alcohol from the previous example and 29.5mg (0.29mmol) of triethylamine in 2mL of methylene chloride at OOC is added dropwise 29mg (0.25mmol) of mesyl chloride. The mixture is stirred further until TLC shows no remaining alcohol. The mixture is partitioned between ethyl acetate, ice water, brine, and 2N HC1. The organic phase is separated, dried over sodium sulfate, filtered, and evaporated to give the corresponding mesylate derivative, which is used without further purification.

PREPARATIVE EXAMPLE 39 02CO H

H

00 0 A mixture of 136.2mg (0.195mmol) of the mesylate prepared in the previous example and 58.3mg (0.389mmol) of sodium iodide in 3mL of acetone is stirred at ambient temperature until TLC indicates that the reaction is complete. The mixture is partitioned between ethyl acetate, ice water, and brine. The organic phase is separated, dried over sodium sulfate, filtered, and evaporated to give the corresponding iodide derivative, which is used without further purification.

Lh WO 99/20270 PCT/US98/22111 109 PREPARATIVE EXAMPLE 02COH ,N N O /-CONH2 ON 2 O T f A mixture of 142.6mg (0.195mmol) of the iodide prepared in the previous example, 62.1mg (0.195mmol) of dabco acetamide triflate salt, and 50mg (0.195mmol) of silver triflate in 2mL of acetonitrile is stirred at room temperature until TLC shows no remaining iodide. The insoluble materials are removed by filtration through celite, washed well with acetonitrile, and the filtrate is evaporated. The residue is taken up in methylene chloride and the product is precipitated by the addition of ether. The precipitate is collected and dried in vacuo to give the desired product.

Example 1

HO

0 N NS ®./-CONH2 eo o N D o A mixture of 107.4mg (0.lmmol) of the product of the previous example, 15.7mg (0.06mmol) of triphenylphosphine, 21.1mg (0.02mmol) of tetrakistriphenylphosphinepalladium(0), 15.9mg (0.1 mmol) of 2-ethylhexanoic acid, and 0.22mL of a 0.5M solution of sodium-2-ethylhexanoate in ethyl acetate in 2mL of DMF is stirred at WO 99/20270 PCT/US98/22111 110 ambient temperature for one hour. Ether is added to the mixture and the separated material is collected by centrifugation and decantation of the supernatant. The solid is washed similarly with ether and dried. The product is purified by ion exchange chromatography on MACROPREP resin with 5% NaCl solution, followed by desalting on AMBERCHROM CG 161 resin. The eluant containing the product is concentrated in vacuo and freeze-dried to give the final product.

Example 2 HO Ci CONH2 HH H c 0to Following the procedure outlined in preparative example 36, with the phenol prepared in preparative example 28, and subsequently following the processes of preparative examples 37-40, and example 1, the product depicted is prepared.

Example 3

CO

2 CH3 _CONH2 WO 99/20270 PCT/US98/22111 111 Following the procedure outlined in preparative example 36, with the phenol prepared in preparative example 19, and subsequently following the processes of preparative examples 37-40, and example 1, the product depicted is prepared.

Example 4

HO

HH

H

3 CI 0 0 C( CONH2 Following the procedure outlined in preparative example 36, with the phenol prepared in preparative example 17, and subsequently following the processes of preparative examples 37-40, and example 1, the product depicted is prepared.

Example 0 CONH2 Cl WO 99/20270 PCT/US98/22111 112 Following the procedure outlined in preparative example 36, with the mercaptobenzothiazole derivative prepared according to US 5,496,816, and subsequently following the processes of preparative examples 37-40, and example 1, the product depicted is prepared.

Example 6

HO

HH

H

3

C

2 /79 CONH2 Following the procedure outlined in preparative example 36, with the phenol prepared in preparative example 15, and subsequently following the processes of preparative examples 37-40, and example 1, the product depicted is prepared.

Example 7

HO

HH

H

3

C

C O

NO

,n [CONH 2

I

WO 99/20270 PCT/US98/22111 113 Following the procedure outlined in preparative example 36, with the phenol prepared in preparative example 7, and subsequently following the processes of preparative examples 37-40, and example 1, the product depicted is prepared.

Example 8 Following the procedure outlined in preparative example 36, with the phenol prepared in preparative example 20, and subsequently following the process of example 1, except that the purification is by reverse phase plate layer chromatography, the product depicted is prepared.

Claims (23)

1. A compound represented by formula I: Rrr HH H 3 C 0 N Z I CO 2 M or a pharmaceutically acceptable salt thereof, wherein: Z represents (R) 3 o (R) 3 (R) 3 a x (R) 3 N--S d* c* X represents CH 2 CHR, C=CHR, O, S, SO, SO 2 CO, CO 2 OCO, or NR; CO 2 M represents a carboxylic acid, a carboxylate anion counter balanced by a counterion, a pharmaceutically acceptable ester group or a carboxylic acid protected by a protecting group; Rrr represents hydrogen, -C1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R i groups; P represents hydrogen, hydroxyl, F or hydroxyl protected by a hydroxyl-protecting group; WO 99/20270 PCT/US98/22111 115 each R is independently selected from: -Q; hydrogen; halo; -CN; -NO 2 -NRaRb; -ORc; -SRC; -C(O)NRaRb; C(O)ORh; -S(O)Rc; -SO 2 Rc; -SO 2 NRaRb; -NRaSO 2 Rb; -C(O)Ra; OC(O)Ra; -OC(O)NRaRb; -NRaC(O)NRbRc; -NRaCO 2 Rh; -OC 2 Rh; NRaC(O)Rb; -C1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four Rd groups; and -C3-7 cycloalkyl, unsubstituted or substituted with one to four Rd groups; with the proviso that at least one R is present which contains at least one positive charge; each Ra, Rb and Rc independently represents hydrogen, -CI-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four Rd groups, or -C3- 7 cycloalkyl, unsubstituted or substituted with one to four Rd groups; or Ra and Rb taken together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one or more of O, S, NRc, with Rc as defined above, or said ring being unsubstituted or substituted with one to four R i groups; or Rb and Rc taken together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one to three of O, S, NRa, with Ra as defined above, or said ring being unsubstituted or substituted with one to four R i groups; each Rd independently represents halo; -CN; -NO 2 -NReRf; -ORg; -SRE; -CONReRf; -COORE; -SORs; -SO 2 Rg; -SO 2 NReRf; NReSO 2 Rf; -CORe; -NRe CORf; -OCORe; -OCONReRf; -NReCONRfRg; NReCO 2 Rh; -OCO 2 Rh; -C(NRe)NRfRg; -NReC(NH)NRfRg; -NReC(NR)Rg; or -Q; Re, Rf and Rg represent hydrogen; -CI-6 straight- or branched-chain alkyl unsubstituted or substituted with one to four Ri groups; or Re and R f taken together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one WO 99/20270 PCT/US98/22111 116 to three of O, S, or NRg with Rg as defined above, said ring being unsubstituted or substituted with one to four R i groups; each R i independently represents halo; -CN; -N02; phenyl; -NHS0 2 Rh; -ORh, -SRh; -N(Rh) 2 -N+(Rh) 3 -C(O)N(Rh) 2 SO 2 N(Rh) 2 heteroaryl; heteroarylium; -CO 2 Rh; -C(0)Rh; -OCORh; NHCORh; guanidinyl; carbamimidoyl or ureido; each Rh independently represents hydrogen, a -CI-6 straight or branched-chain alkyl group, a -C3-C6 cycloalkyl group or phenyl, or when two Rh groups are present, said Rh groups may be taken in combination and represent a 4-6 membered saturated ring, optionally interrupted by one or two of O, S, S02, NH and NCH 3 Q is selected from the group consisting of: (CH 2 )b NN 1 N N, N -R x and -NRXRYRz cc" L (CH 2 )a wherein: a and b are 1, 2 or 3; L- is a pharmaceutically acceptable counterion; (x represents O, S or NRs; P, 8, X, g and a represent CRt, N or N+Rs, provided that no more than one of P, 8, X, g and a is N+RS; R* is selected from the group consisting of: dY e e- g wherein: d represents O, S or NRk; e, g, x, y and z represent CR m N or N+Rk, provided that WO 99/20270 PCT/US98/22111 117 no more than one of e, g, x, y and z in any given structure represents N+Rk; Rk represents hydrogen; -CI- 6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four Ri groups; or (CH 2 )nQ where n 1, 2 or 3 and Q is as previously defined; each Rm independently represents a member selected from the group consisting of: hydrogen; halo; -CN; -NO 2 -NRnRo; -ORn; SRn; -CONRnRo; -COORh; -SORn; -SO 2 Rn; -SO 2 NRnRo; -NRnSO 2 Ro; CORn; -NRnCORo; -OCORn; -OCONRnRo; -NRnCO 2 Rh; -NRnCONRoRh; -OCO 2 Rh; -CNRnNRoRh; -NRnCNHNRoRh; -NRnC(NRo)Rh; -C1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four Ri groups; -C3- 7 cycloalkyl, unsubstituted or substituted with one to four Ri groups; and -(CH 2 )nQ where n and Q are as defined above; R n and Ro represent hydrogen, phenyl; -CI- 6 straight- or branched-chain alkyl unsubstituted or substituted with one to four Ri groups; each Rs independently represents hydrogen; phenyl or -C 1 -6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four Ri groups; each Rt independently represents hydrogen; halo; phenyl; -CN; -NO 2 -NRuRv; -ORu; -SRu; -CONRuRv; -COORh; -SORu; -SO 2 Ru; -SO 2 NRuR; -NRuSO 2 Rv; -CORu; -NRuCORv; -OCORu; -OCONRuRv; -NRuCO 2 RV; -NRUCONRRW; -OCO 2 Rv; -C1- 6 straight- or branched- chain alkyl, unsubstituted or substituted with one to four Ri groups; Ru and R v represent hydrogen or -CI-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four Ri groups; WO 99/20270 PCT/US98/22111 118 or Ru and Rv together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one or more of O, S, NR w or said ring being unsubstituted or substituted with one to four R i groups; each R w independently represents hydrogen; -C1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R i groups; C3-6 cycloalkyl optionally substituted with one to four R i groups; phenyl optionally substituted with one to four Ri groups, or heteroaryl optionally substituted with 1-4 Ri groups; or Rh and R w taken together with any intervening atoms represent a 5-6 membered saturated ring, optionally interrupted by one or two of O, S, S02, NH or NCH3; R x represents hydrogen or a C1-8 straight- or branched- chain alkyl, optionally interrupted or terminated by one or two of O, S, SO, SO2, NRw, N+RhRw, or said chain being unsubstituted or substituted with one to four of halo, CN, N02, ORw, SRw, SORw, SO2RW, NRhRw, N+(Rh) 2 Rw, C(O)NRhRw, SO2NRhRw, CO2Rw, OC(O)Rw, OC(O)NRhRw, NRhC(O)Rw, NRhC(O)NRhRw, phenyl or heteraryl, said phenyl and heteroaryl being optionally substituted with from one to four Ri groups or with one to two C1-3 straight- or branched- chain alkyl groups, said alkyl groups being unsubstituted or substituted with one to four R i groups; RY and Rz represent hydrogen; phenyl; -C1- 6 straight or branched chain alkyl, unsubstituted or substituted with one to four Ri groups, and optionally interrupted by O, S, NRw, N+RhRw or or R x and RY together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by O, S, S02, NRw N+RhRw or unsubstituted or substituted with 1 4 Ri groups, WO 99/20270 PCT/US98/22111 119 and when Rx and RY together represent a 4-6 membered ring as defined above, Rz is as defined above or Rz represents an additional saturated 4-6 membered ring fused to the ring represented by Rx and RY taken together, optionally interrupted by O, S, NRw or said rings being unsubstituted or substituted with one to four R i groups.

2. A compound in accordance with claim 1 wherein CO2M represents a carboxylate anion.

3. A compound in accordance with claim 1 wherein one R represents a group which contains a positively charged moiety, and the remaining R groups are selected from hydrogen and C1-6 straight or branched chain alkyl, unsubstituted or substituted with one to four Rd groups.

4. A compound in accordance with claim 3 wherein one R represents a group containing a positively charged moiety and the remaining R groups are hydrogen. A compound in accordance with claim 1 wherein the R groups contain from 1-3 positive charges.

6. A compound in accordance with claim 5 wherein the R groups contain two positive charges, balanced by a carboxylate anion and a negatively charged counterion.

7. A compound in accordance with claim 1 wherein one R group represents a -C 1 -6 straight or branched chain alkyl group, substituted with one to four Rd groups, wherein one Rd group represents or Q.

8. A compound in accordance with claim 1 wherein Q is selected from the group consisting of: WO 99/20270 PCT/US98/22111 -120 (CH2)b N II and /N L (CH 2 )a

9. A compound in accordance with claim 8 wherein wherein Q represents: (CH2)b l N N\N- RX L (CH 2 )a a and b are as originally defined, and Rx represents a member selected from the group consisting of: hydrogen or a C1-8 straight- or branched- chain alkyl, optionally interrupted or terminated by one or two of O, S, SO, S02, NRw, N+RhRw, or said chain being unsubstituted or substituted with one to four of halo, CN, N02, ORw, SRw, SORw, SO2R, NRhRw, N+(Rh) 2 Rw, C(O)NRhRw, SO 2 NRhRw, CO2R w OC(O)Rw, OC(0)NRhRw, NRhC(O)Rw, NRhC(0)NRhRw, phenyl, or heteroaryl, said phenyl and heteroaryl being optionally substituted with from one to four R i groups or with one to two C1-3 straight- or branched- chain alkyl groups, said alkyl groups being unsubstituted or substituted with one to four RI groups, and Rh, Ri and R w are as originally defined. A compound in accordance with claim 1 wherein Q represents -N+RxRYRz, wherein Rx, RY and Rz are as originally defined.

11. A compound in accordance with claim 1 wherein one R* group is present and is selected from: WO 99/20270 PCT/US98/22111 121 e- X- 1x and d'y e g d represents NRk; Rk represents -C 1 6 straight or branched chain alkyl; and e, g, x and y represent CRm or N+Rk, with Rk as defined above and R m representing hydrogen.

12. A compound in accordance with claim 1 wherein: CO2M represents a carboxylate anion; one R group which is attached to the naphthosultam platform contains at least one positively charged moiety, and the remaining R groups are selected from hydrogen and C1-6 straight or branched chain alkyl, unsubstituted or substituted with one to four Rd groups. Rd is as originally defined; Rh represents hydrogen or a C 1 -6 straight or branched chain alkyl group; Q is selected from the group consisting of: (CH 2 )b +N I and L (CH 2 )a wherein L- is as originally defined; a and b represent 2, and Rx represents a member selected from the group consisting of: hydrogen or a C1-8 straight- or branched- chain alkyl, optionally interrupted or terminated by one or two of O, S, SO, S02, NRw, N+RhRw, or said chain being unsubstituted or substituted with one to four of halo, CN, N02, ORW, SR w SORw, SO2R, NRhRw, N+(Rh) 2 RW, C(O)NRhRw, SO2NRhRw, CO2Rw, OC(O)Rw, OC(O)NRhRw, NRhC(O)RW, NRhC(O)NRhRw, phenyl, or heteroaryl, said phenyl and heteroaryl being optionally WO 99/20270 PCT/US98/22111 122 substituted with from one to four R i groups or with one to two C1-3 straight- or branched- chain alkyl groups, said alkyl groups being unsubstituted or substituted with one to four R i groups; R* is selected from: 1 I and d.y e. wherein d represents NRk; Rk represents -Cl-6 straight or branched chain alkyl; and e, g, x and y represent CR m or N+Rk, with Rk as defined above and Rm representing hydrogen.

13. A compound in accordance with claim 1 represented by formula Ia: HO HRH H 3 0 N/ R O N Ia CO 2 M S O or a pharmaceutically acceptable salt thereof, wherein: CO2M represents a carboxylate anion; one R contains a positively charged moiety, and the other R groups are selected from hydrogen and C1-6 straight or branched chain alkyl, unsubstituted or substituted with one to four Rd groups; R d is as originally defined; Q is selected from the group consisting of: WO 99/20270 PCT/US98/22111 123 (CH 2 )b N fN and N<\N-Rx \P x L (CH 2 )a wherein a and b are as originally defined, and R x represents a member selected from the group consisting of: hydrogen or a C1-8 straight- or branched- chain alkyl, optionally interrupted or terminated by one or two of O, S, SO, SO2, NRW, N+RhRw, or said chain being unsubstituted or substituted with one to four of halo, CN, NO2, ORW, SRw, SORw, SO2RW, NRhRw, N+(Rh) 2 Rw, C(O)NRhRw, SO2NRhRW, CO2R W OC(O)Rw, OC(O)NRhRw, NRhC(O)Rw, NRhC(O)NRhRW, phenyl, or heteroaryl, said phenyl and heteroaryl being optionally substituted with from one to four Ri groups or with one to two C1-3 straight- or branched- chain alkyl groups, said alkyl groups being unsubstituted or substituted with one to four R i groups; Rh represents hydrogen or a C1-6 straight or branched chain alkyl group; R w is as originally defined; R* is selected from: 11 and d d y e wherein d represents NRk; Rk represents -C1-6 straight or branched chain alkyl; and e, g, x and y represent CRm or N+Rk, with Rk as defined above and R m representing hydrogen.

14. A compound in accordance with claim 1 represented by formula Ib: WO 99/20270 PCT/US98/22111 124 b CO2M S I b 0 0 O or a pharmaceutically acceptable salt thereof, wherein: CO2M represents a carboxylate anion; one R group is attached to the naphthosultam platform which contains a positively charged moiety, and the other R group is selected from hydrogen and C1-6 straight or branched chain alkyl, unsubstituted or substituted with one to four Rd groups; Rd is as originally defined; Q is selected from the group consisting of: (CH2)b r c0 r, 1^ c tE' I and ON N- RX PsB \ap N L (CH 2 )a wherein a and b are as originally defined, and Rx represents a member selected from the group consisting of: hydrogen or a C1-8 straight- or branched- chain alkyl, optionally interrupted or terminated by one or two of O, S, SO, SO2, NRw, N+RhRw, or said chain being unsubstituted or substituted with one to four of halo, CN, N02, ORw, SRw, SORw, SO2R w NRhRw, N+(Rh) 2 Rw, C(O)NRhRw, SO2NRhRw, CO2R w OC(O)Rw, OC(O)NRhRw, NRhC(O)Rw, NRhC(O)NRhRw, phenyl, or heteroaryl, said phenyl and heteroaryl being optionally substituted with from one to four R i groups or with one to two C1-3 straight- or branched- chain alkyl groups, said alkyl groups being unsubstituted or substituted with one to four R i groups; WO 99/20270 PCT/US98/22111 125 Rh represents hydrogen or a C1-6 straight or branched chain alkyl group; R W is as originally defined; R* is selected from: f and d'y e9 wherein d represents NRk; Rk represents -Ci-6 straight or branched chain alkyl; and e, g, x and y represent CR m or N+Rk, with Rk as defined above and Rm representing hydrogen. Within this subset, all other variables are as originally defined with respect to formula I. A compound in accordance with claim 1 represented by formula Ic: HO HH R H 3 C O N COM Ic O R 0 or a pharmaceutically acceptable salt thereof, wherein: CO2M represents a carboxylate anion; one R group is attached to the naphthosultam platform which contains a positively charged moiety, and the other R group is selected from hydrogen, halo and CI-6 straight or branched chain alkyl, unsubstituted or substituted with one to four Rd groups; Rd is as originally defined; Q is selected from the group consisting of: WO 99/20270 PCT/US98/22111 -126 (CH2)b N" r o (N-X R N and L (CH 2 )a wherein a and b are as originally defined, and Rx represents a member selected from the group consisting of: hydrogen or a C1-8 straight- or branched- chain alkyl, optionally interrupted or terminated by one or two of O, S, SO, SO2, NRw, N+RhRw, or said chain being unsubstituted or substituted with one to four of halo, CN, N02, ORw, SRw, SORw, SO 2 RW, NRhRw, N+(Rh) 2 RW, C(O)NRhRW, SO2NRhRw, CO2RW, OC(O)Rw, OC(0)NRhRw, NRhC(0)Rw, NRhC(0)NRhRw, phenyl, or heteroaryl, said phenyl and heteroaryl being optionally substituted with from one to four Ri groups or with one to two C1-3 straight- or branched- chain alkyl groups, said alkyl groups being unsubstituted or substituted with one to four R i groups; Rh represents hydrogen or a C1-6 straight or branched chain alkyl group; R w is as originally defined; R* is selected from: and dy e wherein d represents NRk; Rk represents -C1- 6 straight or branched chain alkyl; and e, g, x and y represent CRm or N+Rk, with Rk as defined above and R m representing hydrogen.

16. A compound in accordance with claim 1 represented by formula Id: WO 99/20270 PCT/US98/22111 -127 HO H 3 C R R 0 N COgM Id 0S 0 O or a pharmaceutically acceptable salt thereof, wherein: CO2M represents a carboxylate anion; one R group is attached to the naphthosultam platform which contains a positively charged moiety, and the other R group is selected from hydrogen, halo and C1-6 straight or branched chain alkyl, unsubstituted or substituted with one to four Rd groups; Rd is as originally defined; Q is selected from the group consisting of: (CH 2 )b and N N-Rx L (CH 2 )a wherein a and b are as originally defined, and Rx represents a member selected from the group consisting of: hydrogen or a C1-8 straight- or branched- chain alkyl, optionally interrupted or terminated by one or two of O, S, SO, S02, NRw, N+RhRw, or said chain being unsubstituted or substituted with one to four of halo, CN, N02, ORw, SRw, SORw, SO2RW, NRhRw, N+(Rh) 2 RW, C(O)NRhRw, SO2NRhRw, CO2Rw, OC(O)Rw, OC(0)NRhRw, NRhC(0)Rw, NRhC(O)NRhRw, phenyl, or heteroaryl, said phenyl and heteroaryl being optionally substituted with from one to four Ri groups or with one to two C1-3 straight- or branched- chain alkyl groups, said alkyl groups being unsubstituted or substituted with one to four R i groups; WO 99/20270 PCT/US98/22111 128 Rh represents hydrogen or a C1-6 straight or branched group; Rw is as originally defined; R* is selected from: chain alkyl e-. d-- and eS wherein d represents NRk; Rk represents -C1-6 straight or branched chain alkyl; and e, g, x and y represent CR m or N+Rk, with Rk as defined above and R m representing hydrogen.

17. A compound in accordance with claim 1 represented by formula Ie: or a pharmaceutically acceptable salt thereof, wherein: R contains a positively charged moiety selected from the group consisting of: Q, and a C1-6 straight or branched alkyl chain substituted with one Rd group; Rd is independently selected or Q; Q is selected from the group consisting of: WO 99/20270 PCT/US98/22111 129 (CH2)b and N N-Rx L (CH 2 )a wherein a and b are as originally defined, and R x represents a member selected from the group consisting of: hydrogen or a C1-8 straight- or branched- chain alkyl, optionally interrupted or terminated by one or two of O, S, SO, S02, NRw, N+RhRw, or said chain being unsubstituted or substituted with one to four of halo, CN, N02, ORw, SRW, SORw, SO2R w NRhRw, N+(Rh) 2 RW, C(O)NRhRw, SO 2 NRhRw, CO2Rw, OC(O)Rw, OC(O)NRhRw, NRhC(O)Rw, NRhC(O)NRhRw, phenyl, or heteroaryl, said phenyl and heteroaryl being optionally substituted with from one to four R i groups or with one to two C1-3 straight- or branched- chain alkyl groups, said alkyl groups being unsubstituted or substituted with one to four R i groups; R* is selected from: l and an d-y e9. wherein d represents NRk; Rk represents -C -6 straight or branched chain alkyl; and e, g, x and y represent CRm or N+Rk, with Rk as defined above and R m representing hydrogen.

18. A compound in accordance with claim 1 represented by formula If: WO 99/20270 PCT/US98/22111 130 HO R HH H 3 0 N O N 02- If oS 0 or a pharmaceutically acceptable salt thereof, wherein: R contains a positively charged moiety selected from the group consisting of: Q, and a C1- 6 straight or branched alkyl chain substituted with one Rd group; Rd is independently selected or Q; Q is selected from the group consisting of: (CH 2 )b I- "N and N R L (CH 2 )a wherein a and b are as originally defined, and R x represents a member selected from the group consisting of: hydrogen or a C1-8 straight- or branched- chain alkyl, optionally interrupted or terminated by one or two of O, S, SO, SO2, NRw, N+RhRw, or said chain being unsubstituted or substituted with one to four of halo, CN, N02, ORw, SRW, SORw, SO2RW, NRhRw, N+(Rh) 2 Rw, C(0)NRhRw, SO2NRhRw, CO2RW, OC(O)Rw, OC(0)NRhRw, NRhC(0)RW, NRhC(0)NRhRw, phenyl, or heteroaryl, said phenyl and heteroaryl being optionally substituted with from one to four Ri groups or with one to two C1-3 straight- or branched- chain alkyl groups, said alkyl groups being unsubstituted or substituted with one to four R i groups; WO 99/20270 PCT/US98/22111 131 R* is selected from: I- el and PY Yg d-y e- wherein d represents NRk; Rk represents -C1-6 straight or branched chain alkyl; and e, g, x and y represent CR m or N+Rk, with Rk as defined above and Rm representing hydrogen.

19. A compound in accordance with claim 17 wherein: R represents (CH 2 )b -(CH2)1e-N N-R L (CH 2 )a and Rx, a, b and L- are as originally defined. A compound in accordance with claim 1 represented by formula Ig: HO CO 2 M S Ig o-S\\ 0 wherein: R represents WO 99/20270 PCT/US98/22111 -132 (CH 2 )b -(CH2)1-6-N N-Rx e L (CH 2 )a and Rx, a, b and L- are as originally defined.

21. A compound in accordance with claim 1 represented by formula Ih: P H H H 3 C OHC (R) 3 CO 2 M Ih wherein: X represents CH 2 CHR, C=CHR, O, S, SO, SO2, CO, CO 2 OCO, NR; CO2M represents a carboxylate anion; R represents (CH 2 )b -(CH2)1-6-N VN-R x e\ L (CH 2 )a and Rx, a, b and L- are as originally defined.

22. A compound in accordance with claim 1 represented by formula Ii: WO 99/20270 WO 9920270PCTIUS98/22111I 133 (R) 3 C02M represents a carboxylate anion; R represents (CHA) 2)16-N ON Rx L(CH 2 )a and Rx, a, b and L- are as originally defined. represented

23. A compound in accordance with claim 1 by formula Ij: P H 3 C (R) 3 wherein: C02M represents a carboxylate anion; R represents 134 (CH2) and Rx, a, b and L- are as originally defined. 2 4. A compound represented by the structural formula: U H 3 C N+ 'NH 0 E-1 CO 0~\I ai HO HO HH L H 3 0 0- 002 O 'N 0 E-2 *HO+ HO H H H H H3C H 3 C *0 -0 *C0 2 0 S 'ICO 2 Z\ \\j0 0 E-3 1 0 E-4 Me6 [R:\UIBAA]O8619.doc:ACR WO 99/20270 WO 9920270PCT[US98/221 II -135- HOH H HH H 3 CHC 0 N N/ 0 H2N H H F'\ C02- and E-8 WO 99/20270 WO 9920270PCT/tUS98/221 II 136 HO H 3 C CO2- 200o 3HNOO. OOH y OOH OH y OOH OH 200o HY y0CH OHLI II IZZ86SWIJd OZV6O OLZOV66 OM H 3 C H 3 C Co 2 H 3 C. H, H 3 C. Le S S *SSS S S S *.Sc H 3 C. 002- ICO 2 CI-b [R:\LIBAA]08619.doc:ACR HIC L+ C0 2 HOHHLe CQNH 2 HO I NH 2 L H 3 C 0 C(12 \,\AN CO L A 0 [RALIBAA]08619.doc:ACR H 3 C HOH CONH 2 .H 3 CN NH 2 H 3 C wherein L- and L+ are a pharmaceutically acceptable counterionS.

25. A compound in accordance with claim 1 represented by the structural formula: HOH H 3 C 00 0 wherein Q is \)AN 0 [RA-LIBAA]08619.doc:ACR WO 99/20270 WO 9920270PCTIUS98/22111l

141- Table OH PhS F 9 N+10 N11I Ph phenyl FH 2 N yNH 2 N 0 12 9 13 d 14 N N H+ NC+NH H 3 C..W H H3 N. W OH H 3 rl- N+ 16 N+17 SI7~ CH 3 OH 3 CH 3 (9 (9 18KsN~ N+ 19L4 WO 99/20270 WO 9920270PCT/US98/221 11 -142 21S 21(22 b' 23 R N 4 NH 2 H 2 N N rj NH 24 N+ 25 N 4 26 and L- is a pharmaceutically acceptable counterion. 26. A compound represented by the structure: WO 99/20270 WO 9920270PCT/US98/221 11 143 H 3 C NH 2 N+ CH 3 NH 2 N+ HO N+ L-7 B 2 CH 3 HO N+ H 3 C NH 2 N+ CH 3 NH 2 N+ L-H HO p OH 3 HO N+ wherein Q is as defined in the tables and L- represents a pharmaceutically acceptable counterion. WO 99/20270 WO 9920270PCTIUS98/221 11 144 27. A compound in accordance with claim 1 falling within one of the following tables: HOHH jH H H 3 C 00 Table HO Q 27 N+28 N29 N F') N.,Nh I- Liv) L4h H 3 C Table Q NH 2 L-H Q HO N+ PCH 3 L4H WO 99/20270 WO 9920270PCT/US98/221 II 145 HO HO H H N/ 0 N L C02 0 ~S 0 0 Table #Q Q NH 2 HOF 38 N39 HO H H H 3 C N! 0- C02 C~ TableQ OH 41 4] N N43 WO 99/20270 WO 9920270PCT/US98/221 II 146 TABLE NH 2 L- Q HO N+ S Q PH 3 H 3 C' NH 2 L--o HO N+ F (9 L-- WO 99/20270 PCT/US98/2211 I

147- HOH H 3 C 0 N' CO 2 O=Sx 0 OH jC H 3 rN N H 3 C O N CO 2 0 N 0 Q TABLE NH 2 HO r, ,1 CH 3 N+5 N 58) N WO 99/20270 WO 9920270PCT/US98/221 11 -148 H 3 C Table Q NH 2 L- Q HO Np L4 H 3 C' TABLE -r 1-1 PH 3 OH N L-h N N s HO CHON 319VI 6HOY OH 'HN 6171 I I ZZ/86SflhlID OZV6O OLZOV66 Offi,

318-VI +N J/ L-4- N N C H t-4- +N +N OY, ZHN 091 ITI ZV86SflhlJd OZV6O OLZOV66 OM C- N OH 01" ?HN CHO' 318 VI L- +N 1 1 N CHO' L-h L1ND -N Lh +N 0 OH ~HN OCH 'OO21H 191 I I I ZZ/86Sflhl3d OZV6O OLZOV66 OM WO 99/20270 WO 9920270PCTIUS98/221 11 152 wherein L- represents a pharmaceutically acceptable counterion. 28. A compound of structural formula: HO 00 eb ND (D HO HH CONH2 H 3 C HO H H H 3 0 7N o C0 2 CO 2 CH3 /---\(DCONH2 HOHH jH H H 3 C 0 N 02 0 0 c, e C DCONH2 cI E HO H 3 C 'j CONH2 Cl E H 3 C. [R:\LIBAA]08619.doc:ACR 154 29. A method of preparing a carbapenem antibacterial compound, the method being substantially as hereinbefore described with reference to any one of the Preparative Examples excluding any comparative examples. A method of preparing a carbapenem antibacterial compound, the method being substantially as hereinbefore described with reference to any one of the General Synthesis Schemes 1 to 3. 31. A carbapenem antibacterial compound prepared by the method in accordance with claim 29 or claim 32. A compound substantially as hereinbefore described with reference to any one of the Representative Examples. 33. A pharmaceutical composition comprised of a compound in accordance with any one of claims 1 to 28, 31 or 32 in combination with a pharmaceutically acceptable carrier. 34. A pharmaceutical composition produced by combining a compound in 15 accordance with claim 1 with a pharmaceutically acceptable carrier. "35. A method of treating or preventing a bacterial infection in a mammalian patient, the method comprising administering to said patient an effective amount of a compound in accordance with any one of claims 1 to 28, 31 or 32 or of a pharmaceutical composition in accordance with claim 33 or claim 34. 36. A method of treating or preventing a bacterial infection in a mammalian patient, the method comprising administering to said patient an effective amount of a compound in accordance with claim 1. o* 37. A compound in accordance with any one of claims 1 to 28, 31 or 32 or a composition in accordance with claim 33 or claim 34 when used for treating or preventing a bacterial infection in a mammalian patient. 38. Use of a compound in accordance with any one of claims 1 to 28, 31 or 32 in the manufacture of a medicament for treating or preventing a bacterial infection in a mammalian patient. Dated 20 February, 2001 Merck Co., Inc. Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON [R:\LIBAA]08619.doc:ACR